CN109748819A - The preparation method and its method of purification of α-cyanoacrylatealkyl monomer, application - Google Patents
The preparation method and its method of purification of α-cyanoacrylatealkyl monomer, application Download PDFInfo
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- CN109748819A CN109748819A CN201910147933.6A CN201910147933A CN109748819A CN 109748819 A CN109748819 A CN 109748819A CN 201910147933 A CN201910147933 A CN 201910147933A CN 109748819 A CN109748819 A CN 109748819A
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Abstract
The invention discloses the preparation method of α-cyanoacrylatealkyl monomer and its methods of purification, application, belong to technical field of biological material.The present invention is by carrying out polycondensation reaction, depolymerization reaction completion purification for α-cyanoacrylatealkyl monomer crude product；Medical adhesive main component purity > 99% prepared by the present invention；Diffusion closure performance is good, and polymeric membrane good toughness, heat of polymerization are low, adhesion strength is big etc. meets clinical needs.Product has the advantage that are as follows: 1. prevent bacterium infection；2. accelerating wound healing time；3. reducing pain；4. improving cosmetic result；5. facilitating operation.
Description
Technical field
The invention belongs to technical field of biological material, and in particular to the preparation method of α-cyanoacrylatealkyl monomer and its
Method of purification, application.
Background technique
Three kinds of isobutyl alpha-cyanoacrylate, α-cyanoacrylaten-butyl, α-n-octylcyanoacrylate alpha-cyanos third
Olefin(e) acid alkyl ester monomer can be micro with skin surface due to there are two electron-withdrawing groups of cyano [- CN] and carbonyl [- C=O]
Carbonyl [- OH] and amino [- NH in moisture and body fluid2] etc. anionic groups reaction, alpha-cyanoacrylate can be caused rapidly
Isobutyl ester monomer polymerization, after 5-15 seconds skin surface formed protective film, can by skin close adhesion, make tissue and bacterium every
From.The adhesive strength of glue film is greater than the natural pulling force of wound, can be by skin close adhesion, and in fibrin ferment and fibrinous
Play the role of hemostasis, blood coagulation immediately under effect；In biological assessment, through overtesting its cytotoxicity, intradermal reaction, skin
Skin sensitization, haemolysis, genetoxic, implantation, subchronic toxicity meet the requirements, and decompose, drain in vivo etc. in addition, also having
Feature；More excellent performance enables him for blood vessel bonding, intestinal tube and oesophagus in bonding of coincideing, skin incision bonding, diffusate
Hemostasis etc. in closing, the repairing of defective tissue, the closing in fistula hole and organ operation.
Have now been found that isobutyl alpha-cyanoacrylate, α-cyanoacrylaten-butyl, α-three kinds of alpha-cyanoacrylate n-octyl
For α-cyanoacrylatealkyl monomer since purity not enough causes glue-line brittleness big, solidfied material is harder, stops blooding insufficient, glues
Conjunction intensity is not high, and the time that falls off is longer.
Summary of the invention
Technical problem to be solved by the invention is to provide a kind of preparation method of α-cyanoacrylatealkyl monomer and
Its method of purification, application, it is intended to be asked by the purity that polycondensation reaction, depolymerization reaction solve α-cyanoacrylatealkyl monomer
Topic, and solve that glue-line brittleness is big, and solidfied material is harder, stops blooding insufficient, and adhesive strength is not high, and the time that falls off is longer etc. to ask
Topic.
In order to solve the above technical problems, the technical solution used in the present invention is: a kind of α-alkyl cyanoacrylate list
The method of purification of body, which is characterized in that by the way that α-cyanoacrylatealkyl monomer crude product is carried out polycondensation reaction, depolymerization
Purification is completed in reaction；
Wherein, the auxiliary reagent that polycondensation reaction uses has formaldehyde, catalyst piperidines, lauryl sodium sulfate, purified water
And basic catalyst phosphoric acid；The auxiliary reagent that depolymerization reaction uses has basic catalyst phosphoric acid, plasticizer phosphate trimethylbenzene
Ester, hydroquinone of polymerization retarder, dehydrating agent P2O5And reagent hydroquinone, P in receiving bottle2O5, sulfur dioxide protect gas.
A further technical solution lies in the auxiliary reagent proportions that the polycondensation reaction uses are as follows:
α-cyanoacrylatealkyl monomer crude product: Xg
Formaldehyde: X/141 × 30/0.37g
Catalyst piperidines: X/141 × 85 × 0.007/0.02g
Lauryl sodium sulfate: X/141g
Purified water: X/141 × 100g
Basic catalyst phosphoric acid: X/141 × 1.5/1.685ml
Wherein X > 0.
A further technical solution lies in the auxiliary reagent proportions that the depolymerization reaction uses are as follows:
α-cyanoacrylatealkyl monomer condensation product: Yg
Basic catalyst phosphoric acid: Y/100ml
Plasticizer tricresyl phosphate: Y/10ml
Hydroquinone of polymerization retarder: 2Y/100g
Dehydrating agent P2O5: 4Y/100g
Reagent in receiving bottle: hydroquinone: Y/100g, P2O5, 2Y/100g, sulfur dioxide protection gas
Wherein, Y > 0.
A further technical solution lies in the method is used for isobutyl alpha-cyanoacrylate, alpha-cyanoacrylate just
Three kinds of butyl ester, α-n-octylcyanoacrylate α-cyanoacrylatealkyl monomer purifications.
A further technical solution lies in, the specific steps are that:
(1) polycondensation reaction
Lauryl sodium sulfate is dissolved with purified water under heating water bath environment, alpha-cyanoacrylate alkane is then added
Then formalin is added dropwise when temperature is 49.3 DEG C in base ester monomer crude product stirring and dissolving, and piperazine is added dropwise when temperature is 50 DEG C
Pyridine catalyst solution is reacted, and accelerates reaction by stirring when temperature is 82 DEG C；In end of reaction be added phosphoric acid in and
α-cyanoacrylatealkyl monomer condensation product is made in product washing by piperidines；
(2) depolymerization reaction
By α-cyanoacrylatealkyl monomer condensation product, tricresyl phosphate, phosphoric acid, hydroquinone of polymerization retarder press than
Example is added in there-necked flask, and receiving bottle condensing recovery fraction is used under oil bath environment, and de-polymerization temperature is controlled at 160 DEG C -180 DEG C
Between, it receives fraction between 80 DEG C -120 DEG C and controls as crude product, depolymerization time in 3-3.5 hour, after the completion in dioxy
Change under conditions of sulphur protects gas and crude product is refined again, oil bath temperature slowly increases, and increases 3 DEG C every time；Collect steaming
Glue of the temperature between 80 DEG C -120 DEG C, weighs glue, is proportionally added into hydroquinone of polymerization retarder and rocks uniformly,
Rubber plug is stoppered, is protected from light, kept dry, purification is completed.
A further technical solution lies in, a kind of preparation method and method of purification of α-cyanoacrylatealkyl monomer,
α-cyanoacrylatealkyl monomer crude product is prepared first with ester exchange reaction.
A further technical solution lies in be used to prepare in isobutyl alpha-cyanoacrylate, ester exchange reaction uses examination
Agent proportion are as follows:
Ethyl cyanoacetate: Zmol
Isobutanol: 2Zmol
The catalyst concentrated sulfuric acid: Zml
Wherein, Z > 0.
A further technical solution lies in preparation steps are as follows:
One, ester-exchange reaction step:
Accurate cyan-acetic ester, isobutanol, the concentrated sulfuric acid of measuring is added in three-necked flask, pays attention to rocking when being added dropwise, with
Anti- local over-concentration；After material adds, there-necked flask is seated in heated at constant temperature magnetic agitation oil bath pan, installation is with thermometer
Rectifying column, then thermometer is inserted into there-necked flask and surveys kettle temperature, another port is stoppered with rubber plug, is connected in rectifying column dropping liquid pipe port
Condenser pipe is connect, graduated cylinder is placed in condenser pipe liquid outlet received down ethyl alcohol；Open condensed water and oil bath pan switch, oil bath temperature
Degree is just set as 60 DEG C, and temperature heats up after stablizing, and increases within every ten minutes 10 DEG C, after oil bath temperature reaches 90 DEG C, is changed to slowly rise
Temperature, every time increase 3 DEG C, when oil bath temperature is raised to 120 DEG C -125 DEG C, start receive ethyl alcohol, control steam temperature in 78 DEG C -83 DEG C it
Between；With the increase of ethyl alcohol receipts amount, temperature is gradually increasing, and when steaming temperature rise to 90 DEG C, is started to collect isobutanol, is collected isobutyl
The steaming temperature general control of alcohol is between 90 DEG C -108 DEG C, and between 130 DEG C -160 DEG C, isobutanol is received for oil bath temperature control at this time
It after complete, powers off, water source, there-necked flask is taken out to cooling from oil bath, when temperature is down to≤50 DEG C, by liquid in there-necked flask
Body pours into pear shape separatory funnel, is washed with saturated sodium chloride solution；It sufficiently to be rocked when washing, it is quiet then to put back to iron stand
After setting clarification 45 minutes, subnatant is bled off, then washed with 10% Carbon Dioxide sodium solution, bleeds off lower layer after standing 30 minutes
Clear liquid；It is washed again with saturated sodium chloride solution, bleeds off subnatant after standing 45 minutes；Liquid standing arrives in pyriform funnel
When pH value is 7, thick ester cyanoacetic acid isobutyl ester can be obtained；
Two, polycondensation reaction
Into water-bath kettle be added half volume purified water, install thermometer and stirring rod at room temperature to
Quantitative purified water and lauryl sodium sulfate is added in water-bath kettle, opens electric mixer, controls stirring rate about 208
Rev/min or so, it stirs 20-25 minutes, after lauryl sodium sulfate is dissolved completely, adjusts speed of agitator to about 625 revs/min
Thick ester cyanoacetic acid isobutyl ester is added at room temperature, the formalin that concentration is 37%, rate of addition are added after stirring 30 minutes for clock
Control is added dropwise to be uninterrupted, and bath temperature is set as 49.3 DEG C when kettle temperature rises to 50 DEG C, and the piperidines that concentration is 2% is added
Catalyst solution, this reaction are exothermic reaction, and kettle temperature can rise to 75 DEG C or so when reaction；Bath temperature is set at this time as 83.9
DEG C, when thermometer shakes larger, remove thermometer；When water bath temperature rises to 80 DEG C, water bath temperature is set as 82 DEG C,
Stirring rate is reduced to 500 revs/min or so simultaneously, is stirred to react 3 hours, when reaction proceeds to 45 minutes 2 hours, is added
Condensation product is taken out, condensation product is fallen with piperidines, stopping reaction after stirring 15 minutes, closing water-bath kettle in quantitative phosphoric acid
Enter to fill in the enamel basin of purified water, condensation product gradually becomes crisp solid, is broken into pieces with one's fingers and is pounded fine powder in enamel basin
Middle stirring is rinsed, and is poured into mounted Bush's funnel, and vacuum pump is opened, and carries out decompression suction filtration, then more with purified water elution
It is secondary, it filters until not going to the condensation product powder in Buchner funnel in enamel tray after thering is water droplet drippage to filter, title
Measure the poly- isobutyl alpha-cyanoacrylate net weight of condensation product；
Three, depolymerization reaction
In proportion by the poly- isobutyl alpha-cyanoacrylate of condensation product, tricresyl phosphate, phosphoric acid, hydroquinone of polymerization retarder
It is added in there-necked flask, rocks uniformly；Thermometer is installed in oil bath reaction kettle, still head (is denoted as equipped with temperature reading
Steam temperature), condenser pipe, receiving bottle；It opens vacuum pump and opens cooling water after system pressure meets the requirements；At the beginning of oil bath temperature
It is set as 160 DEG C to begin to warm up, adjusts mixing speed, vacuum degree is held in ± 50 mmHg of 3700mmHg；After material is completely melt,
It is appropriate slowly to increase oil bath temperature, start to flow back when steaming temperature and reaching 40 DEG C -50 DEG C, at this time it should be noted that observation adapter
Whether place oozes front-end volatiles, and evaporates temperature and time before recording；Collection is evaporated before after temperature to be distilled is stable to finish, emptying,
Receiving bottle is replaced rapidly in termination of pumping, and into receiving bottle and quantitative hydroquinone and phosphorus pentoxide is added in reaction kettle；It opens
Vacuum pump is opened, stirring rate is adjusted, starts to carry out depolymerization；De-polymerization temperature controls between 160 DEG C -180 DEG C, 80 DEG C of reception -
Fraction is controlled as crude product, depolymerization time in 3-3.5 hour between 120 DEG C；After depolymerization, the oil bath more renewed will
Three-necked flask equipped with crude product is put into oil bath, is loaded onto condensing unit (consistent with morning depolymerizer) and is refined；Oil bath
Temperature is just set as 80 DEG C, adjusts SO2Air inflow is kept for bubble 8-12 per minute, starts to be refined；It is appropriate slowly to increase
Oil bath temperature (increase every time 3 DEG C be advisable) collects steaming temperature in 78 DEG C of pervious fractions, it is preceding evaporate receipts to the greatest extent after, replace receiving bottle,
Adjusting oil bath temperature makes steaming temperature collect glue between 80 DEG C -120 DEG C, and steaming warm highest may not exceed 120 DEG C；When steaming temperature drop
To when steaming 4 DEG C -5 DEG C of temperature lower than highest, turns off oil bath, stop vacuum pump；Device is removed rapidly sends the cleaning of brush room to laundry；Receiving bottle takes
After lower, weighing obtains glue net weight, and being proportionally added into quantitative hydroquinone of polymerization retarder rocks uniformly, stoppers rubber plug, puts to keeping away
It is to be filled at light is dry etc..
A further technical solution lies in the preparation method of above-mentioned α-cyanoacrylatealkyl monomer is on medical adhesive
Application.
The beneficial effects of adopting the technical scheme are that medical adhesive main component purity prepared by the present invention
> 99%；Diffusion closure performance is good, and polymeric membrane good toughness, heat of polymerization are low, adhesion strength is big etc. meets clinical needs.Product
Have the advantage that for；1. preventing bacterium infection；2. accelerating wound healing time；3. reducing pain；4. facilitating operation.
Specific embodiment
Implement below with reference to the present invention, technical scheme in the embodiment of the invention is clearly and completely described, shows
So, described embodiment is only a part of the embodiments of the present invention, instead of all the embodiments.Based in the present invention
Embodiment, every other embodiment obtained by those of ordinary skill in the art without making creative efforts,
It shall fall within the protection scope of the present invention.
In the following description, numerous specific details are set forth in order to facilitate a full understanding of the present invention, but the present invention may be used also
To be implemented using other than the one described here other way, those skilled in the art can be without prejudice in the present invention
Similar popularization is done in the case where culvert, therefore the present invention is not limited by the specific embodiments disclosed below.
Disclosure sets forth a kind of methods of purification of α-cyanoacrylatealkyl monomer, which is characterized in that its pass through by
α-cyanoacrylatealkyl monomer crude product carries out polycondensation reaction, depolymerization reaction completes purification；
Wherein, the auxiliary reagent that polycondensation reaction uses has formaldehyde, catalyst piperidines, lauryl sodium sulfate, purified water
And basic catalyst phosphoric acid；The auxiliary reagent that depolymerization reaction uses has basic catalyst phosphoric acid, plasticizer phosphate trimethylbenzene
Ester, hydroquinone of polymerization retarder, dehydrating agent P2O5And reagent hydroquinone, P in receiving bottle2O5, sulfur dioxide protect gas.
In the preferred embodiment of the present invention, the auxiliary reagent that the polycondensation reaction uses is matched are as follows:
α-cyanoacrylatealkyl monomer crude product: Xg
Formaldehyde: X/141 × 30/0.37g
Catalyst piperidines: X/141 × 85 × 0.007/0.02g
Lauryl sodium sulfate: X/141g
Purified water: X/141 × 100g
Basic catalyst phosphoric acid: X/141 × 1.5/1.685ml
Wherein X > 0.
In the preferred embodiment of the present invention, the auxiliary reagent proportion that the depolymerization reaction uses is
α-cyanoacrylatealkyl monomer condensation product: Xg
Basic catalyst phosphoric acid: Y/100ml
Plasticizer tricresyl phosphate: Y/10ml
Hydroquinone of polymerization retarder: 2Y/100g
Dehydrating agent P2O5: 4Y/100g
Reagent in receiving bottle: hydroquinone: Y/100g, P2O5: 2Y/100g, sulfur dioxide protect gas
Wherein, Y > 0.
In the preferred embodiment of the present invention, the method is used for isobutyl alpha-cyanoacrylate, the positive fourth of alpha-cyanoacrylate
Three kinds of ester, α-n-octylcyanoacrylate α-cyanoacrylatealkyl monomer purifications.
In the preferred embodiment of the present invention, the specific steps are that:
(1) polycondensation reaction
By lauryl sodium sulfate water-solubleization under heating water bath environment, α-alkyl cyanoacrylate is then added
Then formalin is added dropwise when temperature is 49.3 DEG C in monomer crude product stirring and dissolving, and piperidines is added dropwise when temperature is 50 DEG C and urges
Agent solution is reacted, and accelerates reaction by stirring when temperature is 82 DEG C；In end of reaction be added phosphoric acid in and piperazine
Pyridine washes product to obtain α-cyanoacrylatealkyl monomer condensation product；
(2) depolymerization reaction
By α-cyanoacrylatealkyl monomer condensation product, tricresyl phosphate, phosphoric acid, hydroquinone of polymerization retarder press than
Example is added in there-necked flask, and receiving bottle condensing recovery fraction is used under oil bath environment, and de-polymerization temperature is controlled at 160 DEG C -180 DEG C
Between, it receives fraction between 80 DEG C -120 DEG C and controls as crude product, depolymerization time in 3-3.5 hour, after the completion in dioxy
Change under conditions of sulphur protects gas and crude product is refined again, oil bath temperature slowly increases, and increases 3 DEG C every time；Collect steaming
Glue of the temperature between 80 DEG C -120 DEG C, weighs glue, is proportionally added into hydroquinone of polymerization retarder and rocks uniformly,
Rubber plug is stoppered, is protected from light, kept dry, purification is completed.
In the preferred embodiment of the present invention, the preparation method and method of purification of α-cyanoacrylatealkyl monomer utilize ester
Exchange reaction prepares α-cyanoacrylatealkyl monomer crude product.
It in the preferred embodiment of the present invention, is used to prepare in isobutyl alpha-cyanoacrylate, the used reagent of ester exchange reaction
Proportion are as follows:
Ethyl cyanoacetate: Zmol
Isobutanol: 2Zmol
The catalyst concentrated sulfuric acid: Zml
Wherein, Z > 0.
In the preferred embodiment of the present invention, preparation step are as follows:
One, ester-exchange reaction step:
Accurate cyan-acetic ester, isobutanol, the concentrated sulfuric acid of measuring is added in three-necked flask, pays attention to rocking when being added dropwise, with
Anti- local over-concentration；After material adds, there-necked flask is put into heated at constant temperature magnetic agitation oil bath pan, installation is with thermometer
Rectifying column, then thermometer is inserted into there-necked flask and surveys kettle temperature, another port is stoppered with rubber plug, is connected in rectifying column dropping liquid pipe port
Condenser pipe is connect, graduated cylinder is placed in condenser pipe liquid outlet received down ethyl alcohol；Open condensed water and oil bath pan switch, oil bath temperature
Degree is just set as 60 DEG C, and temperature heats up after stablizing, and increases within every ten minutes 10 DEG C, after oil bath temperature reaches 90 DEG C, is changed to slowly rise
Temperature, every time increase 3 DEG C, when oil bath temperature is raised to 120 DEG C -125 DEG C, start receive ethyl alcohol, control steam temperature in 78 DEG C -83 DEG C it
Between；With the increase of ethyl alcohol receipts amount, temperature is gradually increasing, and when steaming temperature rise to 90 DEG C, is started to collect isobutanol, is collected isobutyl
The steaming temperature general control of alcohol is between 90 DEG C -108 DEG C, and between 130 DEG C -160 DEG C, isobutanol is received for oil bath temperature control at this time
It after complete, powers off, water source, there-necked flask is taken out to cooling from oil bath, when temperature is down to≤50 DEG C, by liquid in there-necked flask
Body pours into pear shape separatory funnel, is washed with saturated sodium chloride solution；It sufficiently to be rocked when washing, it is quiet then to put back to iron stand
After setting clarification 45 minutes, subnatant is bled off, then washed with 10% Carbon Dioxide sodium solution, bleeds off lower layer after standing 30 minutes
Clear liquid；It is washed again with saturated sodium chloride solution, bleeds off subnatant after standing 45 minutes；Liquid standing arrives in pyriform funnel
When pH value is 7, thick ester cyanoacetic acid isobutyl ester can be obtained；
Two, polycondensation reaction
The purified water of half volume is added into water-bath kettle, installs thermometer and stirring rod at room temperature to reaction
A certain amount of purified water and lauryl sodium sulfate is added in kettle, opens electric mixer, controls about 208 revs/min of left sides of stirring rate
The right side is stirred 20-25 minute, and after lauryl sodium sulfate is dissolved completely, adjusting speed of agitator is to about 625 revs/min, room temperature
It is lower that thick ester cyanoacetic acid isobutyl ester is added, the formalin that concentration is 37% is added after stirring 30 minutes, rate of addition control is
It is uninterrupted to be added dropwise, bath temperature is set as 49.3 DEG C when kettle temperature rises to 50 DEG C, the piperidine catalyst that concentration is 2% is added
Solution, this reaction are exothermic reaction, and kettle temperature can rise to 75 DEG C or so when reaction；Bath temperature is set at this time as 83.9 DEG C, temperature
When meter shakes larger, thermometer is removed；When water bath temperature rises to 80 DEG C, water bath temperature is set as 82 DEG C, is dropped simultaneously
Low stirring rate is stirred to react 3 hours to 500 revs/min or so, and when reaction proceeds to 45 minutes 2 hours, quantitative phosphorus is added
Acid neutralizes piperidines, stops reaction after stirring 15 minutes, closes water-bath and blender takes out reaction kettle from water-bath, claim
After amount condensation amount of substance, condensation product is poured into the enamel basin for filling purified water, condensation product gradually becomes crisp solid, by it
It breaks into pieces with one's fingers and is pounded fine powder and is stirred in enamel basin and rinse, pour into mounted Bush's funnel, open vacuum pump, carry out
Decompression filters, then is eluted repeatedly with purified water, filters until will not be in Buchner funnel after having water droplet drippage to filter
Condensation product powder is gone in enamel tray, and weighing obtains the poly- isobutyl alpha-cyanoacrylate net weight of condensation product；
Three, depolymerization reaction
In proportion by the poly- isobutyl alpha-cyanoacrylate of condensation product, tricresyl phosphate, phosphoric acid, hydroquinone of polymerization retarder
It is added in there-necked flask, rocks uniformly, be put into oil bath pan, install thermometer, still head (is denoted as equipped with temperature reading
Steam temperature), condenser pipe, receiving bottle；It opens vacuum pump and opens cooling water after system pressure meets the requirements；At the beginning of oil bath temperature
It is set as 160 DEG C to begin to warm up, adjusts mixing speed, vacuum degree is held in ± 50 mmHg of 3700mmHg；After material is completely melt,
It is appropriate slowly to increase oil bath temperature, start to flow back when steaming temperature and reaching 40 DEG C -50 DEG C, at this time it should be noted that observation adapter
Whether place oozes front-end volatiles, and evaporates temperature and time before recording；Collection is evaporated before after temperature to be distilled is stable to finish, emptying,
Termination of pumping, replaces rapidly receiving bottle, and quantitative hydroquinone and phosphorus pentoxide are housed in receiving bottle and in reaction kettle；It opens
Vacuum pump adjusts stirring rate, starts to carry out depolymerization；De-polymerization temperature controls between 160 DEG C -180 DEG C, receives 80 DEG C -120
Fraction is controlled as crude product, depolymerization time in 3-3.5 hour between DEG C；After depolymerization, the oil bath more renewed will be filled
There is the three-necked flask of crude product to be put into oil bath, loads onto condensing unit (consistent with morning depolymerizer) and refined；Oil bath temperature
Degree is just set as 80 DEG C, adjusts SO2Air inflow is kept for bubble 8-12 per minute, starts to be refined；It is appropriate slowly to increase oil
Bath temperature (increase every time 3 DEG C be advisable) collects steaming temperature in 78 DEG C of pervious fractions, it is preceding evaporate receipts to the greatest extent after, replace receiving bottle, adjust
Fuel-economizing bath temperature makes steaming temperature collect glue between 80 DEG C -120 DEG C, and steaming warm highest may not exceed 120 DEG C；When steam temperature drop extremely
When steaming 4 DEG C -5 DEG C of temperature lower than highest, turns off oil bath, stop vacuum pump；Device is removed rapidly sends the cleaning of brush room to laundry；Receiving bottle is removed
Afterwards, it weighs and obtains glue net weight, be proportionally added into hydroquinone of polymerization retarder and rock uniformly, stopper rubber plug, put to being protected from light drying
Place etc. is to be filled.
In the preferred embodiment of the present invention, the preparation method of above-mentioned α-cyanoacrylatealkyl monomer is on medical adhesive
Using.
Embodiment
1, the purified water of half is added in water-bath kettle and lauryl sodium sulfate is stirred, dodecane
After base sodium sulphate dissolves completely, speed of agitator is adjusted to about 625 revs/min, cyanoacetic acid isobutyl ester 2000g is added, stirs 30 points
Clock.Formalin 1150.09g of the concentration for 37% is being added, rate of addition control is added dropwise to be uninterrupted, bath temperature is set
It is set to 49.3 DEG C.When kettle temperature rises to 50 DEG C, it is added 2% piperidine catalyst solution, kettle temperature can rise to 75 DEG C of left sides when reaction
It is right.Bath temperature is set at this time as 83.9 DEG C.Stirring rate is reduced to 500 revs/min or so simultaneously, is stirred to react 3 hours.
When reaction proceeds to 45 minutes 2 hours, with piperidines 421.99g in the quantitative phosphoric acid of addition, stops reacting after stirring 15 minutes, obtain
It is being dried to condensation product (poly- isobutyl alpha-cyanoacrylate).By poly- isobutyl alpha-cyanoacrylate 1100g, tricresyl phosphate
Toluene ester 110g, phosphatase 11 1g, hydroquinone of polymerization retarder 22g are added in there-necked flask in the ratio in product formula, are rocked
It is even.Vacuum pump is opened, oil bath temperature is just set as 160 DEG C and begins to warm up, and adjusts mixing speed, vacuum degree is held in 3700mmHg
±50mmHg.De-polymerization temperature controls between 160 DEG C -180 DEG C, receives fraction between 80 DEG C -120 DEG C and solves as crude product
Poly- time control is in 3-3.5 hours.It is refined after depolymerization, oil bath temperature is set as 80 DEG C, adjusts SO2Air inflow,
Kept for 8-12 per minute, bubble, the appropriate oil bath temperature (increasing 3 DEG C every time is advisable) that slowly increases collects steaming temperature in 78 DEG C
Pervious fraction, it is preceding evaporate receipts to the greatest extent after, replace receiving bottle, collect oil bath temperature and steam fraction at temperature between 80 DEG C -120 DEG C, connect
It is finished by product, it is closed to be kept in dark place.
Wherein, polycondensation reaction ingredient is carried out according to the following table
Polycondensation reaction list of ingredients
Example 1:
Purified water 992.9g, lauryl sodium sulfate 9.93g are added in water-bath kettle to be mixed, revolving speed 530 is transported
Turn 40 minutes, cyanoacetic acid isobutyl ester 1400g is added, revolving speed 580 operates 40 minutes, and formaldehyde 805.1g is added, and is heated in kettle warm
2% piperidines 295.4g is added in 50 DEG C of degree, shuts down first 15 minutes addition phosphoric acid 8.4ml, product condensation product is obtained after shutdown.
Example 2:
Purified water 1134.8g, lauryl sodium sulfate 11.35g are added in water-bath kettle to be mixed, revolving speed 530
Cyanoacetic acid isobutyl ester 1600g is added in operating 40 minutes, and revolving speed 580 operates 40 minutes, and formaldehyde 920.1g is added, is heated in kettle
2% piperidines 337.6g is added in temperature 50 C, shuts down first 15 minutes addition phosphatase 11 0.1ml, product condensation product is obtained after shutdown.
Example 3:
Purified water 1276.6g, lauryl sodium sulfate 12.77g are added in water-bath kettle to be mixed, revolving speed 530
Cyanoacetic acid isobutyl ester 1800g is added in operating 40 minutes, and revolving speed 580 operates 40 minutes, and formaldehyde 1035.08g is added, is heated to kettle
2% piperidines 379.79g is added in interior temperature 50 C, shuts down first 15 minutes addition phosphatase 11 1.36ml, and product contracting is obtained after shutdown
Close object.
Example 4:
Purified water 1418.44g, lauryl sodium sulfate 14.18g are added in water-bath kettle to be mixed, revolving speed
530 operatings 40 minutes, are added cyanoacetic acid isobutyl ester 2000g, and revolving speed 580 operates 40 minutes, and formaldehyde 1150.09g, heating is added
To 50 DEG C of temperature in the kettle, 2% piperidines 421.99g is added, shuts down first 15 minutes addition phosphatase 11 2.63ml, is produced after shutdown
Product condensation product.
Example 5:
Purified water 1560.35g, lauryl sodium sulfate 15.62g are added in water-bath kettle to be mixed, revolving speed
530 operatings 40 minutes, are added cyanoacetic acid isobutyl ester 2200g, and revolving speed 580 operates 40 minutes, and formaldehyde 1265g is added, is heated to kettle
2% piperidines 464.2g is added in interior temperature 50 C, shuts down first 15 minutes addition phosphatase 11 3.75ml, and product condensation is obtained after shutdown
Object.
Example 6:
Purified water 1702.2g, lauryl sodium sulfate 17.04g are added in water-bath kettle to be mixed, revolving speed 530
Cyanoacetic acid isobutyl ester 2400g is added in operating 40 minutes, and revolving speed 580 operates 40 minutes, and formaldehyde 1380g is added, is heated in kettle
2% piperidines 506.4g is added in temperature 50 C, shuts down first 15 minutes addition phosphatase 11 5ml, product condensation product is obtained after shutdown.
Example 7:
Purified water 1844.05g, lauryl sodium sulfate 18.46g are added in water-bath kettle to be mixed, revolving speed
530 operatings 40 minutes, are added cyanoacetic acid isobutyl ester 2600g, and revolving speed 580 operates 40 minutes, and formaldehyde 1495g is added, is heated to kettle
2% piperidines 548.6g is added in interior temperature 50 C, shuts down first 15 minutes addition phosphatase 11 6.25ml, and product condensation is obtained after shutdown
Object.
Example 8:
Purified water 1985.9g, lauryl sodium sulfate 19.88g are added in water-bath kettle to be mixed, revolving speed 530
Cyanoacetic acid isobutyl ester 2800g is added in operating 40 minutes, and revolving speed 580 operates 40 minutes, and formaldehyde 1610g is added, is heated in kettle
2% piperidines 590.8g is added in temperature 50 C, shuts down first 15 minutes addition phosphatase 11 7.5ml, product condensation product is obtained after shutdown.
Example 9:
Purified water 2127.75g, lauryl sodium sulfate 21.3g are added in water-bath kettle to be mixed, revolving speed 530
Cyanoacetic acid isobutyl 3000g is added in operating 40 minutes, and revolving speed 580 operates 40 minutes, and formaldehyde 1725g is added, and is heated in kettle warm
2% piperidines 633g is added in 50 DEG C of degree, shuts down first 15 minutes addition phosphatase 11 8.7ml, product condensation product is obtained after shutdown.
Claims (9)
1. a kind of method of purification of α-cyanoacrylatealkyl monomer, which is characterized in that it is by by alpha-cyanoacrylate alkane
Base ester monomer crude product carries out polycondensation reaction, depolymerization reaction completes purification；
Wherein, the auxiliary reagent that polycondensation reaction uses have formaldehyde, catalyst piperidines, lauryl sodium sulfate, purified water and
Basic catalyst phosphoric acid；The auxiliary reagent that depolymerization reaction uses has basic catalyst phosphoric acid, plasticizer tricresyl phosphate, resistance
Poly- agent hydroquinone, dehydrating agent P2O5And reagent hydroquinone, P in receiving bottle2O5, sulfur dioxide protect gas.
2. the method for purification of α-cyanoacrylatealkyl monomer according to claim 1, which is characterized in that the polycondensation
React the auxiliary reagent proportion used are as follows:
α-cyanoacrylatealkyl monomer crude product: Xg
Formaldehyde: X/141 × 30/0.37g
Catalyst piperidines: X/141 × 85 × 0.007/0.02g
Lauryl sodium sulfate: X/141g
Purified water: X/141 × 100g
Basic catalyst phosphoric acid: X/141 × 1.5/1.685ml
Wherein X > 0.
3. the method for purification of α-cyanoacrylatealkyl monomer according to claim 1, which is characterized in that the depolymerization
React the auxiliary reagent proportion used are as follows:
α-cyanoacrylatealkyl monomer condensation product: Yg
Basic catalyst phosphoric acid: Y/100ml
Plasticizer tricresyl phosphate: Y/10ml
Hydroquinone of polymerization retarder: 2Y/100g
Dehydrating agent P2O5: 4Y/100g
Reagent in receiving bottle: hydroquinone: Y/100g, P2O5, 2Y/100g, sulfur dioxide protection gas
Wherein, Y > 0.
4. the method for purification of α-cyanoacrylatealkyl monomer according to claim 1, which is characterized in that the method
For to three kinds of isobutyl alpha-cyanoacrylate, α-cyanoacrylaten-butyl, α-n-octylcyanoacrylate alpha-cyano propylene
Acid alkyl ester monomer purification.
5. the method for purification of α-cyanoacrylatealkyl monomer according to claim 1, which is characterized in that its specific step
Suddenly are as follows:
(1) polycondensation reaction
Lauryl sodium sulfate is dissolved with purified water under heating water bath environment, α-cyanoacrylatealkyl list is then added
Then formalin is added dropwise when temperature is 49.3 DEG C in body crude product stirring and dissolving, and piperidines catalysis is added dropwise when temperature is 50 DEG C
Agent solution is reacted, and accelerates reaction by stirring when temperature is 82 DEG C；In end of reaction be added sulfuric acid in and piperidines, will
Product is washed to obtain α-cyanoacrylatealkyl monomer condensation product；
(2) depolymerization reaction
α-cyanoacrylatealkyl monomer condensation product, tricresyl phosphate, phosphoric acid, hydroquinone of polymerization retarder are proportionally added into
Into there-necked flask, receiving bottle condensing recovery fraction is used under oil bath environment, de-polymerization temperature is controlled between 160 DEG C -180 DEG C, connect
Receiving fraction between 80 DEG C -120 DEG C, as crude product, the depolymerization time controlled in 3-3.5 hour, protected after the completion in sulfur dioxide
Crude product is refined again under conditions of gas, oil bath temperature slowly increases, and increases 3 DEG C every time；Collect steaming temperature in 80 DEG C-
Glue between 120 DEG C, weighs glue, is proportionally added into hydroquinone of polymerization retarder and rocks uniformly, stoppers rubber plug, keep away
Light, kept dry complete purification.
6. a kind of preparation method of α-cyanoacrylatealkyl monomer, which is characterized in that carrying out described in claim 1-5
Before the method for purification of α-cyanoacrylatealkyl monomer, α-cyanoacrylatealkyl monomer is prepared first with ester exchange reaction
Crude product.
7. preparation method according to claim 6, which is characterized in that it is used to prepare isobutyl alpha-cyanoacrylate；Its
In, ester exchange reaction is matched using reagent are as follows:
Ethyl cyanoacetate: Zmol
Isobutanol: 2Zmol
The catalyst concentrated sulfuric acid: Zml
Wherein, Z > 0.
8. preparation method according to claim 7, which is characterized in that its preparation step are as follows:
One, ester-exchange reaction step:
It is accurate to measure cyan-acetic ester, isobutanol, it is added in three-necked flask, the concentrated sulfuric acid is then added dropwise；After being added dropwise to complete, by three
Mouth flask is seated in heated at constant temperature magnetic agitation oil bath pan, and installation has the rectifying column of thermometer, is inserted into there-necked flask and is surveyed kettle temperature,
Another port is stoppered with rubber plug, connects condenser pipe in rectifying column dropping liquid pipe port, graduated cylinder is placed in below condenser pipe liquid outlet
Receive ethyl alcohol；Condensed water and oil bath pan switch are opened, oil bath temperature is just set as 60 DEG C, and temperature is gradually warmed up after stablizing, per very
Clock increases 10 DEG C, after oil bath temperature reaches 90 DEG C, is changed to slowly heat up, and increases 3 DEG C every time, oil bath temperature is raised to 120 DEG C -125
DEG C when, start receive ethyl alcohol, control steam temperature between 78 DEG C -83 DEG C；With the increase of ethyl alcohol receipts amount, temperature is gradually increasing, when
When steaming temperature rise to 90 DEG C, starts to collect isobutanol, collect the steaming temperature control system of isobutanol between 90 DEG C -108 DEG C, at this time oil bath temperature
Degree control after isobutanol harvests, powers off, water source between 130 DEG C -160 DEG C, there-necked flask is taken out to cooling from oil bath,
When temperature is down to≤50 DEG C, liquid in there-necked flask is poured into pear shape separatory funnel, is washed with saturated sodium chloride solution；Washing
When sufficiently to rock, then put back to iron stand stand clarification 45 minutes after, bleed off subnatant, then molten with 10% natrium carbonicum calcinatum
Liquid washing, bleeds off subnatant after standing 30 minutes；It is washed again with saturated sodium chloride solution, bleeds off lower layer after standing 45 minutes
Clear liquid；In pyriform funnel liquid stand to pH value be 7 when, collect to obtain thick ester cyanoacetic acid isobutyl ester；
Two, polycondensation reaction
The purified water of half volume is added into water-bath, reaction kettle is put into pot, thermometer and stirring rod are installed
A certain amount of purified water and lauryl sodium sulfate is added to reaction kettle at room temperature, opens electric mixer, controls stirring rate
About 208 revs/min or so, after stirring is dissolved for 20-25 minute completely to lauryl sodium sulfate, adjusting speed of agitator to about 625 turns/
Minute, thick ester cyanoacetic acid isobutyl ester is added at room temperature, after stirring 30 minutes, the formalin that concentration is 37% is added, speed is added dropwise
Degree control is added dropwise to be uninterrupted, and bath temperature is set as 49.3 DEG C when kettle temperature rises to 50 DEG C, and the piperidines that concentration is 2% is added
Catalyst solution, this reaction are exothermic reaction, and kettle temperature can rise to 75 DEG C or so when reaction；Bath temperature is set at this time as 83.9
DEG C, when thermometer shakes larger, remove thermometer；When water bath temperature rises to 80 DEG C, water bath temperature is set as 82 DEG C, together
When reduce stirring rate to 500 revs/min or so, be stirred to react 3 hours；When reaction proceeds to 45 minutes 2 hours, it is added quantitative
It closes water-bath with piperidines, stopping reaction after stirring 15 minutes in phosphoric acid and blender takes out reaction kettle from water-bath, claim
After amount condensation amount of substance, condensation product is poured into the enamel basin for filling purified water, condensation product gradually becomes crisp solid, is broken
It is broken and be pounded fine powder and stirred in enamel basin and rinse, it pours into mounted Bush's funnel, opens vacuum pump, depressurized
It filters, then is eluted repeatedly with purified water, filtered until not having a water droplet drippage, by the condensation product in Buchner funnel after suction filtration
Powder is gone in enamel tray, and weighing obtains the poly- isobutyl alpha-cyanoacrylate net weight of condensation product；
Three, depolymerization reaction
The poly- isobutyl alpha-cyanoacrylate of condensation product, tricresyl phosphate, phosphoric acid, hydroquinone of polymerization retarder are proportionally added into
In there-necked flask, rock uniformly；It is filled with oil bath into reaction kettle, installs thermometer, still head, condenser pipe, receiving bottle；It opens true
Sky pump, after system pressure meets the requirements, opens cooling water；Oil bath temperature is just set as 160 DEG C and begins to warm up, and adjusts stirring speed
Degree, vacuum degree are held in 3700mmHg ± 50mmHg；It is appropriate slowly to increase oil bath temperature after material is completely melt, as steaming Wen Da
Start to flow back when to 40 DEG C -50 DEG C, at this time it should be noted that whether oozing front-end volatiles at observation adapter, and evaporates temperature before recording
Degree and time；Collection being evaporated before after temperature to be distilled is stable to finish, emptying, termination of pumping, replacing receiving bottle rapidly, receiving bottle is provided with fixed
The hydroquinone and phosphorus pentoxide of amount；Quantitative phosphorus pentoxide is added into reaction kettle, opens vacuum pump, adjusts stirring speed
Rate starts to carry out depolymerization；De-polymerization temperature controls between 160 DEG C -180 DEG C, receives fraction between 80 DEG C -120 DEG C and produces as thick
Product, depolymerization time controlled in 3-3.5 hour；After depolymerization, the three-necked flask equipped with crude product is put in the oil bath more renewed
Enter in oil bath pan, loads onto condensing unit and refined；Oil bath temperature is just set as 80 DEG C, adjusts SO2Air inflow keeps every point of bubble
8-12, clock, start to be refined；The appropriate slow oil bath temperature that increases collects steaming temperature in 78 DEG C of pervious fractions, and preceding evaporate is received to the greatest extent
Afterwards, receiving bottle is replaced, adjusting oil bath temperature makes steaming temperature collect glue between 80 DEG C -120 DEG C, and steaming warm highest may not exceed
120℃；When steaming temperature, which is brought down below highest, steams 4 DEG C -5 DEG C of temperature, turns off oil bath, stop vacuum pump；Device is removed rapidly sends brush room to laundry
Cleaning；After receiving bottle is removed, weighing obtains glue net weight, is proportionally added into quantitative hydroquinone of polymerization retarder and rocks uniformly, stoppers
Rubber plug is put to be filled to being protected from light at dry etc..
9. α-cyanoacrylatealkyl monomer the answering on medical adhesive prepared according to preparation method described in claim 6-8
With.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111714685A (en) * | 2020-07-20 | 2020-09-29 | 秦皇岛市科峰医疗器械有限公司 | Method for preparing medical adhesive from alpha-alkyl cyanoacrylate monomer |
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| CN1391552A (en) * | 1999-11-19 | 2003-01-15 | 科乐医药有限公司 | Transesterification method for making cyanoacrylates |
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