CN108250231A - A kind of synthetic method of raising N, O-bis- (trimethylsilyl) acetamide yield and stability - Google Patents
A kind of synthetic method of raising N, O-bis- (trimethylsilyl) acetamide yield and stability Download PDFInfo
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- CN108250231A CN108250231A CN201810124444.4A CN201810124444A CN108250231A CN 108250231 A CN108250231 A CN 108250231A CN 201810124444 A CN201810124444 A CN 201810124444A CN 108250231 A CN108250231 A CN 108250231A
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- ethylchlorosilane
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- end volatiles
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Abstract
The present invention provides a kind of while improves N, the purity of O-bis- (trimethylsilyl) acetamide and the production method of yield, preparation, charging, synthetic reaction, distillation including trim,ethylchlorosilane；It is described distillation include distill front-end volatiles, distill to obtain finished product；The preparation of the trim,ethylchlorosilane is 2.11 2.22 according to the molar ratio of trim,ethylchlorosilane and acetamide:1, by trim,ethylchlorosilane according to trim,ethylchlorosilane head tank is extracted into, the vacuum degree for starting to keep trim,ethylchlorosilane head tank before feeding is 0.001 0.005MPa.Product BSA prepared by the present invention, product purity are increased to 99.58 99.66%；Amount of impurities and content are reduced, and amine content is 0.20 0.25%；For the once through yield of BSA up to 93.42 93.7%, feed stock conversion is high, and more than 3% is improved compared with the prior art.
Description
The present invention is application number 201510614709.5, the applying date：On September 24th, 2015, denomination of invention：" one kind is simultaneously
The divisional application of raising N, the purity of O-bis- (trimethylsilyl) acetamide and the production method of yield ".
Technical field
N, the purity of O-bis- (trimethylsilyl) acetamide and the production method of yield are improved simultaneously the present invention relates to a kind of,
Belong to technical field of organic synthesis.
Background technology
N, O-bis- (trimethylsilyls) acetamide (hereinafter referred to as BSA), BSA products are used as important medicine intermediate
In preparing cephalosporins medicine and its intermediate, Cefpiramide Acid, synthesizing propanediol cefatrizine, synthesis 7- Α methoxies are such as synthesized
Four ammonia azoles sulfidomethyl cephalosporanic acid dimethyl esters of base-7- amino-3- methyl, synthesis 7-7 α of beta-amino-methoxyl group-3- [（1- first
Base -1H-TETRAZOLE -5- bases）Sulfidomethyl] -3- cephem -4- diphenylmethyl carboxylates etc.；Synthesis of selective cholesterol absorption inhibitor
Bulk pharmaceutical chemicals ezetimibe；As the passivation of chromosorb and the modifying agent of sample polar group, conventional chromatogram is used to a variety of
The compound that analysis cannot carry out qualitative and quantitative analysis is analyzed to obtain satisfied result.In recent years with China's organosilicon
The rapid perfect, development of chemical technology, makes organo-silicon compound as pharmaceutical synthesis reagent and the correlation research of intermediate
Most attention is obtained.BSA is increasingly used widely in organic synthesis, particularly to containing unsaturation in compound structure
Key, hydroxyl, carbonyl, carboxyl, amino and the protection of other functional groups, BSA, which has been played, more importantly to be acted on.
BSA or most common trimethyl silicon type protective agent are mainly used for amino acid, the silanization for completing acid, alcohol and amide
Protection, is neutral silanes protective agent, with low toxicity, easily reaction, the easily properties such as removing, in analytical chemistry, organic synthesis, drug
And natural substance modified etc. application is paid more and more attention.
The shortcomings of the prior art is summarized as follows：
（1）Reaction time is long；
（2）Reaction temperature is high；
（3）Product BSA purity is low, purity not more than 99.4%；For detaching and detecting the MEMS cell capture cores of cancer cell
Piece must use the BSA of purity 99.5 (GC) more than % in use, and otherwise testing result is without in all senses；Other several notes
Penetrate with cephalosporin analog antibiotic synthesis must use purity 99.5 (GC) more than % BSA, otherwise human body injection after side reaction especially
Severe side reaction occurs even to occur dead again and again；
（4）Impurity content is high in product；
（5）Product yield is relatively low, and the yield not more than 90% of the prior art, feed stock conversion is low；
（6）Product bin stability is poor, places a period of time product and colour changed into yellow occurs, have floccule etc..
Invention content
The present invention is provided a kind of while improves N to solve more than technical problem, O-bis- (trimethylsilyl) acetamide it is pure
The production method of degree and yield, to realize following goal of the invention：
（1）Reaction time is short；
（2）Condensate temperature when reaction and rectifying is reduced, reaction temperature is reduced to less than 40 DEG C；Rectifying constantly receives finished product
Condensate temperature is reduced to 73 DEG C；
（3）Product BSA purity is increased to more than 99.5% (GC)；
（4）Amount of impurities is reduced, reduces impurity content, especially reduces amine content in product；
（5）Improve product yield and feed stock conversion；
（6）Product excellent storage stability.
For solution more than technical problem, the technical solution adopted by the present invention is as follows：
It is a kind of to improve N, the purity of O-bis- (trimethylsilyl) acetamide and the production method of yield simultaneously, including trimethylchloro-silicane
Preparation, charging, synthetic reaction, the distillation of alkane；It is described distillation include distill front-end volatiles, distill to obtain finished product.
It is that above-mentioned technical proposal is further improved below：
Described to distill to obtain front-end volatiles, the collection of collection and the second front-end volatiles including the first front-end volatiles, vacuum degree reaches 0.082-
During 0.086MPa, temperature<68 DEG C of condensate liquid is as the first front-end volatiles；Keep vacuum degree and intercept vacuum degree for 0.096~
0.099MPa, after being again turned on steam valve, the condensate liquid of 68.1-70 DEG C of gained is the second front-end volatiles.
Described to distill to obtain finished product, 70.1-73 DEG C of gained condensate liquid of gas phase temperature is finished product.
The preparation of the trim,ethylchlorosilane is 2.11-2.22 according to the molar ratio of trim,ethylchlorosilane and acetamide:1,
By trim,ethylchlorosilane according to trim,ethylchlorosilane head tank is extracted into, start to keep the true of trim,ethylchlorosilane head tank before feeding
Reciprocal of duty cycle is 0.001-0.005MPa.
Acetamide, triethylamine, catalyst are added in synthesis reactor, open stirring, agitator speed is set as by the charging
85-100RPM, after stirring 45-55 minutes, adjustment synthesis reactor vacuum degree is 0.01-0.025MPa.
The acetamide and triethylamine molar ratio 1：2.24-2.33.
The catalyst is 2,6- dimethylanilines, imidazoles；The 2,6- dimethylanilines dosage is acetamide weight
0.17-0.57%。
The imidazoles dosage is the 0.18-0. 64% of acetamide weight.
The synthetic reaction, trim,ethylchlorosilane are added dropwise, and it is 33-39 DEG C to continue to keep reaction temperature, keeps synthesis
Kettle vacuum degree is 0.01-0.025MPa, and circulating pump continues cycling through 120-150 minutes, and reaction terminates.
The selection of catalyst of the present invention, by test of many times, it is determined that the use of dimethylaniline is major catalyst, wherein 2,
6- dimethylanilines are that it is preferable to use other as 2,5- dimethylanilines, 3,4- dimethylanilines, 2,3- dimethylanilines also may be used
It uses；Meanwhile selected imidazoles, as cocatalyst, imidazoles boiling point is higher, it is easy to divide with BSA boiling-point differences away from big when finished product detaches
From.
Beneficial effects of the present invention are：
（1）The method of the present invention is reacted under the conditions of low vacuum, and reaction speed is accelerated, and reaction time of the invention is (from starting to be fed to
Reaction finishes), the reaction time is 4-4.5 hours, and industrialized producing technology is generally 8-18 hours in the prior art.
（2）The method of the present invention, it is 33-39 DEG C that reaction temperature is reduced to by present 40-65 DEG C；Rectification temperature, receives into
Product condensate temperature is reduced to 73 DEG C by 90 DEG C, significantly reduces other side reactions such as decomposition, the polymerization of finished product BSA.
（3）Product BSA prepared by the present invention, product purity are increased to 99.58-99.66%.
（4）Product BSA prepared by the present invention, amount of impurities and content are reduced, amine content 0.20-0.25%.
（5）The method of the present invention, high income, up to 93.42-93.7%, domestic existing yield is no more than the once through yield of BSA
90%；Feed stock conversion is high, and feed stock conversion improves more than 3% compared with the prior art.
（6）Solve the problems, such as that product bin stability is poor
Product prepared by the present invention, excellent storage stability, product purity is 99.47-99.57% (GC) after storage 1 year, and appearance is
Colourless transparent liquid, no floccule.Domestic similar product bin stability is poor, and purity declines 3% after storage 1 year, and product is
It is micro- yellow to faint yellow or even floccule occur.
（7）Connection circulating pump is exported in reactor bottom, the i.e. open the circulation pump after starting to be added dropwise trim,ethylchlorosilane, with
Reactor agitator acts synergistically, and enhances the degree of material mixing, promotes heat and mass；Two filterings are followed by circulating pump
Device, one is used for coarse filtration（Filtering accuracy 100-200 mesh）, one for carefully filtering（Filtering accuracy 300-400 mesh）, filter out life
Into triethylamine hydrochloride, system reacts under homogeneous phase condition, and material contact is more abundant, and reaction effect is good.
（8）It determines trim,ethylchlorosilane, triethylamine and acetamide optimum proportion of materials, determines other two kinds of catalyst most
Good dosage；It determines trim,ethylchlorosilane feed postition, reduces trim,ethylchlorosilane contact with moisture etc., reduce trimethylchloro-silicane
Alkane hydrolyzes.
（9）Avoid the decomposition of BSA in building-up process：In view of BSA synthesize when reaction process particularity and finished product BSA and
The polymer for generating other compounds or silicon-nitrogen-oxygen is easily decomposed in hydrogen chloride effect, must as early as possible will be in hydrogen chloride in reaction process
With fall or remove system.
（10）The blocking of pipeline is reduced, and the reaction speed caused by the blocking of pipeline is overcome to decline：Reaction generation
Triethylamine hydrochloride is easily assembled since particle is thinner, it is easy to blocking pipeline, and be present in reaction system and influence trimethyl
The reaction speed of chlorosilane and acetamide.
Description of the drawings
The technological process of the present invention and equipment are further described below in conjunction with attached drawing and implementation.
Fig. 1 is BSA synthesis technology flow diagrams；
In figure：1- trim,ethylchlorosilane head tanks；The first pipelines of 2- regard cup；3- synthesis reactors；4- circulating pumps；5- first filters；
The second filters of 6-；7- distillation stills；8- packed towers；9- condensers；10- front-end volatiles receiving tanks；11- finished product receiving tanks；12- waterpower
Ejector vacuum pump；13- oil seal type oil-sealed rotary pumps；14- first pressures（Vacuum degree）Site instructions device；The first temperature of 15- is just
Ground instruction device；16- second temperature site instructions devices；The second pipelines of 17- regard cup.18- second pressures（Vacuum degree）Refer on the spot
Showing device；19- third pressure（Vacuum degree）Site instructions device.
Specific embodiment
The preferred embodiment of the present invention is illustrated below, it should be understood that preferred embodiment described herein is only used
In the description and interpretation present invention, it is not intended to limit the present invention.
Embodiment 1 is a kind of to improve N, the purity of O-bis- (trimethylsilyl) acetamide and the production method of yield simultaneously
Reaction carries out in 1000L kettles, and synthesis step is as follows：
（1）The preparation of trim,ethylchlorosilane
With vacuum by 350kg（3222mol）Trim,ethylchlorosilane is extracted into trim,ethylchlorosilane head tank 1, starts the preceding holding that feeds
1 tiny structure of trim,ethylchlorosilane head tank keeps vacuum degree 0.001-0.005MPa.
（2）Charging
By 90kg (1524mol) acetamide, 345kg（3409mol）Triethylamine, 0.15kg2,6- dimethylanilines and 0.25kg miaows
Azoles adds in synthesis reactor 3, opens stirring, and agitator speed is set as 85RPM, and after stirring 45 minutes, adjustment 3 vacuum degree of synthesis reactor is
0.01-0.015MPa。
（3）Add in trim,ethylchlorosilane
Trim,ethylchlorosilane head tank 1 is adjusted to normal pressure, trim,ethylchlorosilane, trim,ethylchlorosilane charge door are added dropwise into kettle
It must be submerged in below 3 liquid level of synthesis reactor at 20-35mm, start that trim,ethylchlorosilane i.e. open the circulation pump is added dropwise to synthesis reactor 3
4, material enters synthesis reactor 3 by circulating pump 4, first filter 5, the second filter 6 successively, in first filter 5, the second mistake
The triethylamine hydrochloride of generation is filtered out in filter 6；Circulation fluid must be submerged in synthesis into 3 circulation line feed inlet of synthesis reactor
Below 3 liquid level of kettle at 20-35mm；
Trim,ethylchlorosilane rate of addition is adjusted, controls 33 DEG C of dropping temperature, trim,ethylchlorosilane control added in 90 minutes.
（4）Synthetic reaction
Trim,ethylchlorosilane is added dropwise, and it is 33 DEG C to continue to keep reaction temperature, and it is 0.01MPa to keep 3 vacuum degree of synthesis reactor, is followed
Ring pump 4 continues cycling through 120 minutes, and reaction terminates.
（5）Distillation
The material valve for leading to synthesis reactor 3 is closed, opens the valve for leading to distillation still 7, open the circulation pump 4, by object in synthesis reactor 3
Material is sent into distillation still 7 and is distilled.
Distill to obtain front-end volatiles
Destilling tower used in distillation be packed tower 8,4 meters of tower height, built-in tetrafluoro filler.
A, the collection of the first front-end volatiles
Hydraulic jet pump 12 is first opened, when vacuum degree reaches 0.082MPa, object in steam heating pot is passed through to 3 chuck of distillation still
Material regards cup 17 by the second pipeline, examines material and steam situation.Work as second pressure（Vacuum degree）Site instructions device 18 is aobvious
After the vacustat shown, before 68 DEG C（That is temperature<68℃）Condensate liquid as front-end volatiles, and evaporated before front-end volatiles are accessed
It taps in closed cans 10, obtains the first front-end volatiles；
B, the collection of the second front-end volatiles
When gas phase temperature is stepped up to 68.1 DEG C, first steam off valve, then switch vacuum system, by water-jet vacuum
Pump 12 is switched to oil seal type oil-sealed rotary pump 13；Oil seal type oil-sealed rotary pump 13 is stable, after vacustat, observation second
16 gas phase temperature situation of change of temperature site instructions device keeps vacuum degree and intercepts vacuum degree as 0.096~0.099MPa, then
After secondary unlatching steam valve, the condensate liquid of 68.1-70 DEG C of gained is also served as in front-end volatiles access front-end volatiles receiving tank 10, obtains second
Front-end volatiles.
Distill to obtain finished product
When gas phase temperature is stepped up to 70.1 DEG C, close 10 valve of front-end volatiles receiving tank and open 11 valve of finished product receiving tank
Door intercepts 70.1-73 DEG C of gained condensate liquid and as finished product and is linked into finished product receiving tank 11.
（6）Finished product packing, storage
It is observed when the temperature raising for observing the display of second temperature site instructions device 16 and by the second pipeline depending on cup 17
From condenser 9 come out condensation flow quantity reduce when, first close distillation still 7 heat steam, when observe the second pipeline regard cup 17
When liquid is almost without dropping down, oil seal type oil-sealed rotary pump 13 is closed, finished product packing storage, low temperature is deposited under the conditions of nitrogen-sealed
Storage.
The BSA products of preparation, once through yield 93.42%, purity (GC) 99.58%.It is shown in Table 1
BSA product quality indicators made from table 1
Product purity is 99.47% (GC) after product is stored 1 year, and appearance is colourless transparent liquid, no floccule.
Embodiment 2 is a kind of to improve N, the purity of O-bis- (trimethylsilyl) acetamide and the production method of yield simultaneously
Reaction carries out in 1000L kettles.Synthesis step is as follows：
（1）The preparation of trim,ethylchlorosilane
380kg (3498mol) trim,ethylchlorosilane is extracted into trim,ethylchlorosilane head tank 1 with vacuum, starts the preceding holding that feeds
1 tiny structure of trim,ethylchlorosilane head tank keeps vacuum degree 0.001-0.005MPa.
（2）Charging
By 100kg（1693mol）Acetamide, 365kg (3607mol) triethylamine, 0.2kg2,6- dimethylanilines and 0.2kg miaows
Azoles adds in synthesis reactor 3, opens stirring, and agitator speed is set as 85RPM, and after stirring 50 minutes, adjustment 3 vacuum degree of synthesis reactor is
0.013MPa。
（3）Add in trim,ethylchlorosilane
Trim,ethylchlorosilane head tank 1 is adjusted to normal pressure, trim,ethylchlorosilane, trim,ethylchlorosilane charge door are added dropwise into kettle
It must be submerged in 20-35cm below 3 liquid level of synthesis reactor；Start that trim,ethylchlorosilane i.e. open the circulation pump 4 is added dropwise to synthesis reactor 3,
Material enters synthesis reactor 3 by circulating pump 4, first filter 5, the second filter 6 successively, is filtered in first filter 5, second
The triethylamine hydrochloride of generation is filtered out in device 6；Circulation fluid must be submerged in synthesis reactor into 3 circulation line feed inlet of synthesis reactor
20-35cm below 3 liquid levels；
Trim,ethylchlorosilane rate of addition is adjusted, controls 34 DEG C of dropping temperature, trim,ethylchlorosilane control added in 100 minutes
It is complete.
（4）Synthetic reaction
Trim,ethylchlorosilane is added dropwise, and it is 34 DEG C to continue to keep reaction temperature, and it is 0.013MPa to keep 3 vacuum degree of synthesis reactor,
Circulating pump 4 continues cycling through 130 minutes, and reaction terminates.
（5）Distillation
The material valve for leading to synthesis reactor 3 is closed, opens the valve for leading to distillation still 7；Open the circulation pump 4, by object in synthesis reactor 3
Material is sent into distillation still 7, and adds in the front-end volatiles of embodiment 1.
Distill to obtain front-end volatiles
Destilling tower used in distillation be packed tower 8,4 meters of tower height, built-in tetrafluoro filler.
A, the collection of the first front-end volatiles
Hydraulic jet pump 12 is first opened, when vacuum degree reaches 0.084MPa, object in steam heating pot is passed through to 7 chuck of distillation still
Material, examines material depending on cup 17 by the second pipeline and steams situation.Work as second pressure（Vacuum degree）Site instructions device 18 is aobvious
After the vacustat shown, before 68 DEG C of gained（<68℃）Condensate liquid as front-end volatiles, and by front-end volatiles access front-end volatiles connect
In closed cans 10, the first front-end volatiles are obtained；
B, the collection of the second front-end volatiles
When gas phase temperature is stepped up to 68.1 DEG C, first steam off valve, then switch vacuum system, by water-jet vacuum
Pump 12 is switched to oil seal type oil-sealed rotary pump 13.Oil seal type oil-sealed rotary pump 13 is stable, after vacustat, observation second
16 gas phase temperature situation of change of temperature site instructions device keeps vacuum degree and intercepts vacuum degree as 0.096~0.099MPa；Again
After secondary unlatching steam valve, the condensate liquid of 68.1-70 DEG C of gained is also served as in front-end volatiles access front-end volatiles receiving tank 10, obtains second
Front-end volatiles.
Distill to obtain finished product
When gas phase temperature is stepped up to 70.1 DEG C, close 10 valve of front-end volatiles receiving tank and open 11 valve of finished product receiving tank
Door intercepts 70.1-73 DEG C, and gained condensate liquid is as finished product and is linked into finished product receiving tank 11.
（6）Finished product packing, storage
It is observed when the temperature raising for observing the display of second temperature site instructions device 16 and by the second pipeline depending on cup 17
From condenser 9 come out condensation flow quantity reduce when, first close distillation still 7 heat steam, when observe the second pipeline regard cup 17
When liquid is almost without dropping down, oil seal type oil-sealed rotary pump 13 is closed, finished product packing storage, low temperature is deposited under the conditions of nitrogen-sealed
Storage.The product of preparation：Once through yield 93.51%, purity (GC) 99.59%.It is shown in Table 2
Product quality indicator made from table 2
Product purity is 99.49% (GC) after product is stored 1 year, and appearance is colourless transparent liquid, no floccule.
Embodiment 3 is a kind of to improve N, the purity of O-bis- (trimethylsilyl) acetamide and the production method of yield simultaneously
Reaction carries out in 1000L kettles, and synthesis step is as follows：
（1）The preparation of trim,ethylchlorosilane
With vacuum by 420kg（3866mol）Trim,ethylchlorosilane is extracted into trim,ethylchlorosilane head tank 1, starts the preceding holding that feeds
1 tiny structure of trim,ethylchlorosilane head tank keeps vacuum degree 0.001-0.005MPa.
（2）Charging
By 110kg (1862mol) acetamide, 400kg（3953mol）Triethylamine, 0.3kg2,6- dimethylanilines and 0.2kg miaows
Azoles adds in synthesis reactor 3, opens stirring, and agitator speed is set as 90RPM.After stirring 50 minutes, adjustment 3 vacuum degree of synthesis reactor is
0.014MPa。
（3）Add in trim,ethylchlorosilane
Trim,ethylchlorosilane head tank 1 is adjusted to normal pressure.Trim,ethylchlorosilane, trim,ethylchlorosilane charge door are added dropwise into kettle
It must be submerged in 20-35cm below 3 liquid level of synthesis reactor；Start that trim,ethylchlorosilane i.e. open the circulation pump 4 is added dropwise to synthesis reactor 3,
Material enters synthesis reactor 3 by circulating pump 4, first filter 5, the second filter 6 successively, is filtered in first filter 5, second
The triethylamine hydrochloride of generation is filtered out in device 6；Circulation fluid must be submerged in synthesis reactor into 3 circulation line feed inlet of synthesis reactor
20-35cm below 3 liquid levels；
Trim,ethylchlorosilane rate of addition is adjusted, controls 35 DEG C of dropping temperature, trim,ethylchlorosilane control added in 100 minutes
It is complete.
（4）Synthetic reaction
Trim,ethylchlorosilane is added dropwise, and it is 35 DEG C to continue to keep reaction temperature, and it is 0.015MPa to keep 3 vacuum degree of synthesis reactor,
Circulating pump 4 continues cycling through 130 minutes, and reaction terminates.
（5）Distillation
The material valve for leading to synthesis reactor 3 is closed, opens the valve for leading to distillation still 7, open the circulation pump 4, by object in synthesis reactor 3
Material is sent into distillation still 7, and adds in the front-end volatiles of embodiment 2.
Distill to obtain front-end volatiles
Destilling tower used in distillation be packed tower 8,4 meters of tower height, built-in tetrafluoro filler.
A, the collection of the first front-end volatiles
Hydraulic jet pump 12 is first opened, when vacuum degree reaches 0.085MPa, object in steam heating pot is passed through to 7 chuck of distillation still
Material, examines material depending on cup 17 by the second pipeline and steams situation；Work as second pressure（Vacuum degree）Site instructions device 18 is aobvious
After the vacustat shown, before 68 DEG C of gained condensate liquid（<68℃）Be used as front-end volatiles, and by front-end volatiles access front-end volatiles connect
In closed cans 10, the first front-end volatiles are obtained；
B, the collection of the second front-end volatiles
When gas phase temperature is stepped up to 68.1 DEG C, first steam off valve, then switch vacuum system, by water-jet vacuum
Pump 12 is switched to oil seal type oil-sealed rotary pump 13.Oil seal type oil-sealed rotary pump 13 is stable, after vacustat, observation second
16 gas phase temperature situation of change of temperature site instructions device keeps vacuum degree and intercepts vacuum degree as 0.096~0.099MPa；Again
After secondary unlatching steam valve, the condensate liquid of 68.1-70 DEG C of gained is also served as in front-end volatiles access front-end volatiles receiving tank 10, obtains second
Front-end volatiles.
Distill to obtain finished product
When gas phase temperature is stepped up to 70.1 DEG C, close 10 valve of front-end volatiles receiving tank and open 11 valve of finished product receiving tank
Door intercepts 70.1-73 DEG C of gained condensate liquid, as finished product and is linked into finished product receiving tank 11.
（6）Finished product packing, storage
It is observed when the temperature raising for observing the display of second temperature site instructions device 16 and by the second pipeline depending on cup 17
From condenser 9 come out condensation flow quantity reduce when, first close distillation still 7 heat steam, when observe the second pipeline regard cup 17
When liquid is almost without dropping down, oil seal type oil-sealed rotary pump 13 is closed, finished product packing storage, low temperature is deposited under the conditions of nitrogen-sealed
Storage.The product of preparation, once through yield 93.59%, purity (GC) 99.60%.It is shown in Table 3
Product quality indicator made from table 3
Product purity is 99.51% (GC) after product is stored 1 year, and appearance is colourless transparent liquid, no floccule.
Embodiment 4 is a kind of to improve N, the purity of O-bis- (trimethylsilyl) acetamide and the production method of yield simultaneously
Reaction carries out in 1000L kettles, and synthesis step is as follows：
（1）The preparation of trim,ethylchlorosilane
460kg (4234mol) trim,ethylchlorosilane is extracted into trim,ethylchlorosilane head tank 1 with vacuum, starts the preceding holding that feeds
1 tiny structure of trim,ethylchlorosilane head tank keeps vacuum degree 0.001-0.005MPa.
（2）Charging
By 120kg（2031mol）Acetamide, 440kg (4348mol) triethylamine, 0.3kg2,6- dimethylanilines and 0.3kg miaows
Azoles adds in synthesis reactor 3, opens stirring, and agitator speed is set as 90RPM.After stirring 50 minutes, adjustment 3 vacuum degree of synthesis reactor is
0.016MPa。
（3）Add in trim,ethylchlorosilane
Trim,ethylchlorosilane head tank 1 is adjusted to normal pressure.Trim,ethylchlorosilane, trim,ethylchlorosilane charge door are added dropwise into kettle
It must be submerged in 20-35cm below 3 liquid level of synthesis reactor；Start that trim,ethylchlorosilane i.e. open the circulation pump 4 is added dropwise to synthesis reactor 3,
Material enters synthesis reactor 3 by circulating pump 4, first filter 5, the second filter 6 successively, is filtered in first filter 5, second
The triethylamine hydrochloride of generation is filtered out in device 6；Circulation fluid must be submerged in synthesis reactor into 3 circulation line feed inlet of synthesis reactor
20-35cm below 3 liquid levels；
Trim,ethylchlorosilane rate of addition is adjusted, controls 37 DEG C of dropping temperature, trim,ethylchlorosilane control added in 110 minutes
It is complete.
（4）Synthetic reaction
Trim,ethylchlorosilane is added dropwise, and it is 37 DEG C to continue to keep reaction temperature, and it is 0.016MPa to keep 3 vacuum degree of synthesis reactor,
Circulating pump 4 continues cycling through 150 minutes, and reaction terminates.
（5）Distillation
The material valve for leading to synthesis reactor 3 is closed, opens the valve for leading to distillation still 7.Open the circulation pump 4, by object in synthesis reactor 3
Material is sent into distillation still 7, and adds in the front-end volatiles of embodiment 3.
Distill to obtain front-end volatiles
Destilling tower used in distillation be packed tower 8,4 meters of tower height, built-in tetrafluoro filler.
A, the collection of the first front-end volatiles
Hydraulic jet pump 12 is first opened, when vacuum degree reaches 0.085MPa, object in steam heating pot is passed through to 7 chuck of distillation still
Material, examines material depending on cup 17 by the second pipeline and steams situation.Work as second pressure（Vacuum degree）Site instructions device 18 is aobvious
After the vacustat shown, before 68 DEG C of gained condensate liquid（<68℃）Be used as front-end volatiles, and by front-end volatiles access front-end volatiles connect
In closed cans 10；
B, the collection of the second front-end volatiles
When gas phase temperature is stepped up to 68.1 DEG C, first steam off valve, then switch vacuum system, by water-jet vacuum
Pump 12 is switched to oil seal type oil-sealed rotary pump 13.Oil seal type oil-sealed rotary pump 13 is stable, after vacustat, observation second
16 gas phase temperature situation of change of temperature site instructions device keeps vacuum degree and intercepts vacuum degree as 0.096~0.099MPa.Again
After secondary unlatching steam valve, the condensate liquid of 68.1-70 DEG C of gained is also served as in front-end volatiles access front-end volatiles receiving tank 10.
When gas phase temperature is stepped up to 70.1 DEG C, close 10 valve of front-end volatiles receiving tank and open finished product receiving tank 11
Valve intercepts 70.1-73 DEG C of gained condensate liquid, as finished product and is linked into finished product receiving tank 11.
（6）Finished product packing, storage
It is observed when the temperature raising for observing the display of second temperature site instructions device 16 and by the second pipeline depending on cup 17
From condenser 9 come out condensation flow quantity reduce when, first close distillation still 7 heat steam, when observe the second pipeline regard cup 17
When liquid is almost without dropping down, oil seal type oil-sealed rotary pump 13 is closed, finished product packing storage, low temperature is deposited under the conditions of nitrogen-sealed
Storage.The product of preparation, once through yield 93.62%, purity (GC) 99.63%.It is shown in Table 4
Product quality indicator made from table 4
Product purity is 99.54% (GC) after product is stored 1 year, and appearance is colourless transparent liquid, no floccule.
Embodiment 5 is a kind of to improve N, the purity of O-bis- (trimethylsilyl) acetamide and the production method of yield simultaneously
Reaction carries out in 1000L kettles, and synthesis step is as follows：
（1）The preparation of trim,ethylchlorosilane
With vacuum by 470kg（4326mol）Trim,ethylchlorosilane is extracted into trim,ethylchlorosilane head tank 1, starts the preceding holding that feeds
1 tiny structure of trim,ethylchlorosilane head tank keeps vacuum degree 0.001-0.005MPa.
（2）Charging
By 120kg (2031mol) acetamide, 460kg（4546mol）Triethylamine, 0.45kg2,6- dimethylanilines and 0.4kg miaows
Azoles adds in synthesis reactor 3, opens stirring, and agitator speed is set as 100RPM.After stirring 55 minutes, 3 vacuum degree of synthesis reactor is adjusted
For 0.022MPa.
（3）Add in trim,ethylchlorosilane
Trim,ethylchlorosilane head tank 1 is adjusted to normal pressure, trim,ethylchlorosilane, trim,ethylchlorosilane charge door are added dropwise into kettle
It must be submerged in 20-35cm below 3 liquid level of synthesis reactor；Start that trim,ethylchlorosilane i.e. open the circulation pump 4 is added dropwise to synthesis reactor 3,
Material enters synthesis reactor 3 by circulating pump 4, first filter 5, the second filter 6 successively, is filtered in first filter 5, second
The triethylamine hydrochloride of generation is filtered out in device 6；Circulation fluid must be submerged in synthesis reactor into 3 circulation line feed inlet of synthesis reactor
20-35cm below 3 liquid levels；
Trim,ethylchlorosilane rate of addition is adjusted, controls 38 DEG C of dropping temperature, trim,ethylchlorosilane control added in 110 minutes
It is complete.
（4）Synthetic reaction
Trim,ethylchlorosilane is added dropwise, and it is 38 DEG C to continue to keep reaction temperature, and it is 0.022MPa to keep 3 vacuum degree of synthesis reactor,
Circulating pump 4 continues cycling through 150 minutes, and reaction terminates.
（5）Distillation
The material valve for leading to synthesis reactor 3 is closed, opens the valve for leading to distillation still 7.Open the circulation pump 4, by object in synthesis reactor 3
Material is sent into distillation still 7, and adds in the front-end volatiles of embodiment 4.
Distill to obtain front-end volatiles
Destilling tower used in distillation be packed tower 8,4 meters of tower height, built-in tetrafluoro filler.
A, the collection of the first front-end volatiles
Hydraulic jet pump 12 is first opened, when vacuum degree reaches 0.082MPa, object in steam heating pot is passed through to 7 chuck of distillation still
Material, examines material depending on cup 17 by the second pipeline and steams situation.Work as second pressure（Vacuum degree）Site instructions device 18 is aobvious
After the vacustat shown, before 68 DEG C of gained condensate liquid（<68℃）Be used as front-end volatiles, and by front-end volatiles access front-end volatiles connect
In closed cans 10；
B, the collection of the second front-end volatiles
When gas phase temperature is stepped up to 68.1 DEG C, first steam off valve, then switch vacuum system, by water-jet vacuum
Pump 12 is switched to oil seal type oil-sealed rotary pump 13.Oil seal type oil-sealed rotary pump 13 is stable, after vacustat, observation second
16 gas phase temperature situation of change of temperature site instructions device keeps vacuum degree and intercepts vacuum degree as 0.096~0.099MPa.Again
After secondary unlatching steam valve, the condensate liquid of 68.1-70 DEG C of gained is also served as in front-end volatiles access front-end volatiles receiving tank 10.
Distill to obtain finished product
When gas phase temperature is stepped up to 70.1 DEG C, close 10 valve of front-end volatiles receiving tank and open 11 valve of finished product receiving tank
Door intercepts 70.1-73 DEG C of gained condensate liquid, as finished product and is linked into finished product receiving tank 11.
（6）Finished product packing, storage
It is observed when the temperature raising for observing the display of second temperature site instructions device 16 and by the second pipeline depending on cup 17
From condenser 9 come out condensation flow quantity reduce when, first close distillation still 7 heat steam, when observe the second pipeline regard cup liquid
When body is almost without dropping down, oil seal type oil-sealed rotary pump 13 is closed, finished product packing storage, low temperature stores under the conditions of nitrogen-sealed.
The product prepared, once through yield 93.7%, purity (GC) 99.66%.It is shown in Table 5
Product quality indicator made from table 5
Product purity is 99.57% (GC) after product is stored 1 year, and appearance is colourless transparent liquid, no floccule.
Embodiment 6 is a kind of to improve N, the purity of O-bis- (trimethylsilyl) acetamide and the production method of yield simultaneously
Reaction carries out in 1000L kettles, and synthesis step is as follows：
（1）The preparation of trim,ethylchlorosilane
480kg (4418mol) trim,ethylchlorosilane is extracted into trim,ethylchlorosilane head tank 1 with vacuum, starts the preceding holding that feeds
1 tiny structure of trim,ethylchlorosilane head tank keeps vacuum degree 0.001-0.005MPa.
（2）Charging
By 120kg（2031mol）Acetamide, 470kg (4645mol) triethylamine, 0.5kg2,6- dimethylanilines and 0.45kg miaows
Azoles adds in synthesis reactor 3, opens stirring, and agitator speed is set as 100RPM.After stirring 55 minutes, 3 vacuum degree of synthesis reactor is adjusted
For 0.024MPa.
（3）Add in trim,ethylchlorosilane
Trim,ethylchlorosilane head tank 1 is adjusted to normal pressure, trim,ethylchlorosilane, trim,ethylchlorosilane charge door are added dropwise into kettle
It must be submerged in 20-35cm below 3 liquid level of synthesis reactor；Start that trim,ethylchlorosilane i.e. open the circulation pump 4 is added dropwise to synthesis reactor 3,
Material enters synthesis reactor 3 by circulating pump 4, first filter 5, the second filter 6 successively, is filtered in first filter 5, second
The triethylamine hydrochloride of generation is filtered out in device 6；Circulation fluid must be submerged in synthesis reactor into 3 circulation line feed inlet of synthesis reactor
20-35cm below 3 liquid levels；
Trim,ethylchlorosilane rate of addition is adjusted, controls 37 DEG C of dropping temperature, trim,ethylchlorosilane control added in 110 minutes
It is complete.
（4）Synthetic reaction
Trim,ethylchlorosilane is added dropwise, and it is 37 DEG C to continue to keep reaction temperature, and it is 0.024MPa to keep 3 vacuum degree of synthesis reactor,
Circulating pump 4 continues cycling through 150 minutes, and reaction terminates.
（5）Distillation
The material valve for leading to synthesis reactor 3 is closed, opens the valve for leading to distillation still 7.Open the circulation pump 4, by object in synthesis reactor 3
Material is sent into distillation still 7, and adds in the front-end volatiles of embodiment 5.
Distill to obtain front-end volatiles
Destilling tower used in distillation be packed tower 8,4 meters of tower height, built-in tetrafluoro filler.
A, the collection of the first front-end volatiles
Hydraulic jet pump 12 is first opened, when vacuum degree reaches 0.083MPa, object in steam heating pot is passed through to 7 chuck of distillation still
Material, examines material depending on cup 17 by the second pipeline and steams situation.Work as second pressure（Vacuum degree）Site instructions device 18 is aobvious
After the vacustat shown, before 68 DEG C of gained condensate liquid（<68℃）Be used as front-end volatiles, and by front-end volatiles access front-end volatiles connect
In closed cans 10；
B, the collection of the second front-end volatiles
When gas phase temperature is stepped up to 68.1 DEG C, first steam off valve, then switch vacuum system, by water-jet vacuum
Pump 12 is switched to oil seal type oil-sealed rotary pump 13.Oil seal type oil-sealed rotary pump 13 is stable, after vacustat, observation second
16 gas phase temperature situation of change of temperature site instructions device keeps vacuum degree and intercepts vacuum degree as 0.096~0.099MPa.Again
After secondary unlatching steam valve, the condensate liquid of 68.1-70 DEG C of gained is also served as in front-end volatiles access front-end volatiles receiving tank 10.
Distill to obtain finished product
When gas phase temperature is stepped up to 70.1 DEG C, close 10 valve of front-end volatiles receiving tank and open 11 valve of finished product receiving tank
Door intercepts 70.1-73 DEG C of gained condensate liquid, as finished product and is linked into finished product receiving tank 11.
（6）Finished product packing, storage
It is observed when the temperature raising for observing the display of second temperature site instructions device 16 and by the second pipeline depending on cup 17
From condenser 9 come out condensation flow quantity reduce when, first close distillation still 7 heat steam, when observe the second pipeline regard cup liquid
When body is almost without dropping down, oil seal type oil-sealed rotary pump 13 is closed, finished product packing storage, low temperature stores under the conditions of nitrogen-sealed.
The product prepared, once through yield 93.64%, purity (GC) 99.64%.It is shown in Table 5
Product quality indicator made from table 6
Product purity is 99.56% (GC) after product is stored 1 year, and appearance is colourless transparent liquid, no floccule.
Embodiment 7 is a kind of to improve N, the purity of O-bis- (trimethylsilyl) acetamide and the production method of yield simultaneously
Reaction carries out in 1000L kettles, and synthesis step is as follows：
（1）The preparation of trim,ethylchlorosilane
With vacuum by 490kg（4510mol）Trim,ethylchlorosilane is extracted into trim,ethylchlorosilane head tank 1, starts the preceding holding that feeds
1 tiny structure of trim,ethylchlorosilane head tank keeps vacuum degree 0.001-0.005MPa.
（2）Charging
By 120kg (2031mol) acetamide, 480kg（4744mol）Triethylamine, 0.68kg2,6- dimethylanilines and 0.77kg
Imidazoles adds in synthesis reactor 3, opens stirring, and agitator speed is set as 100RPM, after stirring 55 minutes, adjusts 3 vacuum of synthesis reactor
It spends for 0.025MPa.
（3）Add in trim,ethylchlorosilane
Trim,ethylchlorosilane head tank 1 is adjusted to normal pressure, trim,ethylchlorosilane, trim,ethylchlorosilane charge door are added dropwise into kettle
It must be submerged in 20-35cm below 3 liquid level of synthesis reactor；Start that trim,ethylchlorosilane i.e. open the circulation pump 4 is added dropwise to synthesis reactor 3,
Material enters synthesis reactor 3 by circulating pump 4, first filter 5, the second filter 6 successively, is filtered in first filter 5, second
The triethylamine hydrochloride of generation is filtered out in device 6；Circulation fluid must be submerged in synthesis reactor into 3 circulation line feed inlet of synthesis reactor
20-35cm below 3 liquid levels；
Trim,ethylchlorosilane rate of addition is adjusted, controls 39 DEG C of dropping temperature, trim,ethylchlorosilane control added in 110 minutes
It is complete.
（4）Synthetic reaction
Trim,ethylchlorosilane is added dropwise, and it is 39 DEG C to continue to keep reaction temperature, and it is 0.025MPa to keep 3 vacuum degree of synthesis reactor,
Circulating pump 4 continues cycling through 150 minutes, and reaction terminates.
（5）Distillation
The material valve for leading to synthesis reactor 3 is closed, opens the valve for leading to distillation still 7.Open the circulation pump 4, by object in synthesis reactor 3
Material is sent into distillation still 7, and adds in the front-end volatiles of embodiment 6.
Distill to obtain front-end volatiles
Destilling tower used in distillation be packed tower 8,4 meters of tower height, built-in tetrafluoro filler.
A, the collection of the first front-end volatiles
Hydraulic jet pump 12 is first opened, when vacuum degree reaches 0.086MPa, object in steam heating pot is passed through to 7 chuck of distillation still
Material, examines material depending on cup 17 by the second pipeline and steams situation.Work as second pressure（Vacuum degree）Site instructions device 18 is aobvious
After the vacustat shown, before 68 DEG C of gained condensate liquid（<68℃）Be used as front-end volatiles, and by front-end volatiles access front-end volatiles connect
In closed cans 10；
B, the collection of the second front-end volatiles
When gas phase temperature is stepped up to 68.1 DEG C, first steam off valve, then switch vacuum system, by water-jet vacuum
Pump 12 is switched to oil seal type oil-sealed rotary pump 13.Oil seal type oil-sealed rotary pump 13 is stable, after vacustat, observation second
16 gas phase temperature situation of change of temperature site instructions device keeps vacuum degree and intercepts vacuum degree as 0.096~0.099MPa.Again
After secondary unlatching steam valve, the condensate liquid of 68.1-70 DEG C of gained is also served as in front-end volatiles access front-end volatiles receiving tank 10.
Distill to obtain finished product
When gas phase temperature is stepped up to 70.1 DEG C, close 10 valve of front-end volatiles receiving tank and open 11 valve of finished product receiving tank
Door intercepts 70.1-73 DEG C of gained condensate liquid, as finished product and is linked into finished product receiving tank 11.
（6）Finished product packing, storage
It is observed when the temperature raising for observing the display of second temperature site instructions device 16 and by the second pipeline depending on cup 17
From condenser 9 come out condensation flow quantity reduce when, first close distillation still 7 heat steam, when observe the second pipeline regard cup liquid
When body is almost without dropping down, oil seal type oil-sealed rotary pump 13 is closed, finished product packing storage, low temperature stores under the conditions of nitrogen-sealed.
The product prepared, once through yield 93.61%, purity (GC) 99.60%.It is shown in Table 5
Product quality indicator made from table 7
Product purity is 99.52% (GC) after product is stored 1 year, and appearance is colourless transparent liquid, no floccule.
Unless otherwise indicated, the percentage employed in the present invention is weight percent, ratio of the present invention,
For mass ratio.
Finally it should be noted that：The foregoing is only a preferred embodiment of the present invention, is not intended to restrict the invention,
Although the present invention is described in detail referring to the foregoing embodiments, for those skilled in the art, still may be used
To modify to the technical solution recorded in foregoing embodiments or carry out equivalent replacement to which part technical characteristic.
All within the spirits and principles of the present invention, any modification, equivalent replacement, improvement and so on should be included in the present invention's
Within protection domain.
Claims (2)
1. a kind of synthetic method of raising N, O-bis- (trimethylsilyl) acetamide yield and stability, it is characterised in that：Including three
Preparation, charging, synthetic reaction, the distillation of methylchlorosilane；It is described distillation include distill front-end volatiles, distill to obtain finished product；
Described to distill to obtain front-end volatiles, the collection of collection and the second front-end volatiles including the first front-end volatiles, vacuum degree reaches 0.082-
During 0.086MPa, temperature<68 DEG C of condensate liquid is as the first front-end volatiles；Keep vacuum degree and intercept vacuum degree for 0.096~
0.099MPa, after being again turned on steam valve, the condensate liquid of 68.1-70 DEG C of gained is the second front-end volatiles.
2. the synthesis side of a kind of raising N according to claim 1, O-bis- (trimethylsilyl) acetamide yields and stability
Method, it is characterised in that：Acetamide, triethylamine, catalyst are added in synthesis reactor, open stirring, agitator speed is set by the charging
It is set to 85-100RPM, after stirring 45-55 minutes, adjustment synthesis reactor vacuum degree is 0.01-0.025MPa；
The acetamide and triethylamine molar ratio 1：2.24-2.33；
The catalyst is 2,6- dimethylanilines and imidazoles；
The 2,6- dimethylanilines dosage is the 0.17-0.57% of acetamide weight；
The preparation of the trim,ethylchlorosilane is 2.11-2.22 according to the molar ratio of trim,ethylchlorosilane and acetamide:1, by three
Methylchlorosilane is extracted into trim,ethylchlorosilane head tank with vacuum, starts to keep the vacuum of trim,ethylchlorosilane head tank before feeding
It spends for 0.001-0.005MPa；
The synthetic reaction, trim,ethylchlorosilane are added dropwise, and it is 33-39 DEG C to continue to keep reaction temperature, keeps synthesis reactor true
Reciprocal of duty cycle is 0.01-0.025MPa, and circulating pump continues cycling through 120-150 minutes, and reaction terminates.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810124444.4A CN108250231A (en) | 2015-09-24 | 2015-09-24 | A kind of synthetic method of raising N, O-bis- (trimethylsilyl) acetamide yield and stability |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510614709.5A CN105153218B (en) | 2015-09-24 | 2015-09-24 | It is a kind of to improve N, the purity of O-bis- (trimethylsilyl) acetamide and the production method of yield simultaneously |
| CN201810124444.4A CN108250231A (en) | 2015-09-24 | 2015-09-24 | A kind of synthetic method of raising N, O-bis- (trimethylsilyl) acetamide yield and stability |
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| CN201510614709.5A Division CN105153218B (en) | 2015-09-24 | 2015-09-24 | It is a kind of to improve N, the purity of O-bis- (trimethylsilyl) acetamide and the production method of yield simultaneously |
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| CN201810124443.XA Withdrawn CN108329341A (en) | 2015-09-24 | 2015-09-24 | It is a kind of that N, the method for bis- (trimethylsilyl) acetamides of O-are prepared using composite catalyst |
| CN201510614709.5A Expired - Fee Related CN105153218B (en) | 2015-09-24 | 2015-09-24 | It is a kind of to improve N, the purity of O-bis- (trimethylsilyl) acetamide and the production method of yield simultaneously |
| CN201810123791.5A Withdrawn CN108329340A (en) | 2015-09-24 | 2015-09-24 | A kind of low vacuum, dual catalyst method synthesize N, the method for bis- (trimethylsilyl) acetamides of O- |
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| CN201810124443.XA Withdrawn CN108329341A (en) | 2015-09-24 | 2015-09-24 | It is a kind of that N, the method for bis- (trimethylsilyl) acetamides of O-are prepared using composite catalyst |
| CN201510614709.5A Expired - Fee Related CN105153218B (en) | 2015-09-24 | 2015-09-24 | It is a kind of to improve N, the purity of O-bis- (trimethylsilyl) acetamide and the production method of yield simultaneously |
| CN201810123791.5A Withdrawn CN108329340A (en) | 2015-09-24 | 2015-09-24 | A kind of low vacuum, dual catalyst method synthesize N, the method for bis- (trimethylsilyl) acetamides of O- |
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| CN105597654B (en) * | 2015-12-21 | 2018-11-09 | 浙江衢州正邦有机硅有限公司 | A kind of device and method improving poly- methyltriethoxysilane reaction yield |
| CN114751932B (en) * | 2022-06-16 | 2022-09-09 | 泽升科技(广州)有限公司 | Production method of N, O-bis (trimethylsilyl) acetamide |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3443960C2 (en) * | 1984-12-01 | 1986-12-11 | Dynamit Nobel Ag, 5210 Troisdorf | Process for the preparation of bis-trimethylsilylamides from carboxamides |
| FR2807041B1 (en) * | 2000-03-29 | 2002-11-29 | Atofina | SEMI-CONTINUOUS PROCESS FOR THE PREPARATION OF BIS-SILYL CARBOXYLIC ACID AMIDES |
| DE102004005643B3 (en) * | 2004-02-04 | 2005-07-14 | Degussa Ag | Working up reaction suspensions in an inverted filter centrifuge, useful especially for recovery of triethylamine from preparation of N,O-bis-(trimethylsilyl)acetamide |
| CN1699308A (en) * | 2004-05-20 | 2005-11-23 | 孙友璋 | Process for preparing N,O-bis(trimethylsilyl)acetamide |
| CN1305878C (en) * | 2004-05-20 | 2007-03-21 | 孙友璋 | Process for making N,O-bis tri silicyl trifluoroacetamide |
-
2015
- 2015-09-24 CN CN201810124444.4A patent/CN108250231A/en not_active Withdrawn
- 2015-09-24 CN CN201810124443.XA patent/CN108329341A/en not_active Withdrawn
- 2015-09-24 CN CN201510614709.5A patent/CN105153218B/en not_active Expired - Fee Related
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| CN108329341A (en) | 2018-07-27 |
| CN105153218B (en) | 2018-03-23 |
| CN108329340A (en) | 2018-07-27 |
| CN105153218A (en) | 2015-12-16 |
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