CN207828318U - A kind of continuous synthesis system of non-natural amino acid - Google Patents
A kind of continuous synthesis system of non-natural amino acid Download PDFInfo
- Publication number
- CN207828318U CN207828318U CN201721722764.7U CN201721722764U CN207828318U CN 207828318 U CN207828318 U CN 207828318U CN 201721722764 U CN201721722764 U CN 201721722764U CN 207828318 U CN207828318 U CN 207828318U
- Authority
- CN
- China
- Prior art keywords
- continuous
- entrance
- reaction
- synthesis system
- unit
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Abstract
The utility model provides a kind of continuous synthesis system of non-natural amino acid.The continuous synthesis system includes：Raw material unit without interruption；Continuous grignard reaction member, has feed(raw material)inlet and product exit, feed(raw material)inlet is connected with raw material unit without interruption；Purifier units continuously are quenched, there is object entrance to be purified and purified product to export, object entrance to be purified is connected with product exit；There is saponification unit ester entrance and keto acid product to export, and ester entrance is connected with purified product outlet；And continuous enzymic catalytic reaction unit, there is keto acid product entrance and acids outlet, keto acid product entrance to be connected with keto acid product outlet.The serialization that committed step in non-natural amino acid synthesis is realized by above-mentioned each unit carries out, therefore the thermal energy that is safely and effectively utilized in each reaction, reaction time are also easier to control, it is possible to prevente effectively from enlarge-effect, reduces energy consumption, waste discharge and the cost of processing of purification of products.
Description
Technical field
The utility model is related to the synthesis fields of non-natural amino acid, in particular to a kind of non-natural amino acid
Continuous synthesis system.
Background technology
Amino acid is at least one carboxyl (- COOH) and an amino (- NH2) amphoteric compound, be life albumen
The most basic substance of matter, it is closely bound up with the vital movement of organism.The position of carbon is connected by amino can be divided into α, β, γ etc.
Amino acid can be divided into two class of natural amino acid and non-natural amino acid by its existing way amino acid.Non-natural amino acid is
By artificial synthesized amino acid, because itself or derivative special structure and property agricultural, industry, daily-use chemical industry, food,
Medicine etc. suffers from extensive purposes.
The synthesis of non-natural amino acid has many methods, including but not limited to fermentation method, protein hydrolysis extraction method, chemistry
Synthetic method, biological enzyme produce amino acid, chiral resolution, asymmetric syntheses etc. with genetic engineering means.
Conventional method synthesizes non-natural amino acid, and there are more limitations, for example safety is poor, narrow application range, react item
Part is harsh, and energy consumption is big, of high cost etc..The chemical synthesis process reported nearly all is batch-mode, since reaction condition is more severe
It carves, production process easy tos produce enlarge-effect, by-product is caused to increase, and purity and yield decline.For example, conventional method synthesizes hand
Property center structure be typically all by being catalyzed asymmetric syntheses, asymmetric hydrogenation or method for splitting, wherein catalysis process relates to
And it arrives and uses transition-metal catalyst；Asymmetric hydrogenation needs to use chiral ligand and hydrogen；Method for splitting Atom economy is poor,
Have the product of half useless, and there are it is cumbersome the shortcomings of.
Utility model content
It is existing to solve the main purpose of the utility model is to provide a kind of continuous synthesis system of non-natural amino acid
The non-natural amino acid synthesis problem that safety is poor, yield is low in technology.
To achieve the goals above, one side according to the present utility model provides a kind of company of non-natural amino acid
Continuous synthesis system, including：Raw material unit without interruption；Continuous grignard reaction member, has feed(raw material)inlet and product exit, raw material
Entrance is connected with raw material unit without interruption；Purifier units continuously are quenched, there is object entrance to be purified and purified product to export, wait for
Purification entrance is connected with product exit；There is saponification unit ester entrance and keto acid product to export, and ester entrance is produced with purification
Object outlet is connected；And continuous enzymic catalytic reaction unit, there is keto acid product entrance and acids outlet, keto acid product entrance with
Keto acid product outlet is connected.
Further, above-mentioned raw materials unit without interruption includes：Grignard Reagent feeding mechanism passes through second with feed(raw material)inlet
Automatic dnockout pumps are connected to carry out Grignard Reagent without interruption to continuous grignard reaction member；Ester feeding mechanism, with feed(raw material)inlet
It is connected to carry out ester without interruption to continuous grignard reaction member by the automatic dnockout pumps of third.
Further, above-mentioned Grignard Reagent feeding mechanism includes：Grignard Reagent continuous generation device, passes through with feed(raw material)inlet
Second automatic dnockout pumps are connected to carry out Grignard Reagent without interruption to continuous grignard reaction member；Halogenated alkane feeding mechanism,
It is connected to be carried out continuously to Grignard Reagent continuous generation device by the first automatic dnockout pumps with Grignard Reagent continuous generation device
Supply halogenated alkane；And magnesium metal feeding mechanism, it is connected continuously to be given birth to Grignard Reagent with Grignard Reagent continuous generation device
Magnesium metal without interruption is carried out at device.
Further, above-mentioned magnesium metal feeding mechanism is auger conveyor.
Further, above-mentioned Grignard Reagent continuous generation device is continuous-stirring reactor.
Further, above-mentioned continuous purifier units are quenched to include：Acid quencher feeding mechanism；Extractant feeding mechanism；
First is continuously quenched purifying plant, and there is acid quencher entrance, extractant entrance, the outlet of first purification and object to be purified to enter
Mouthful, acid quencher feeding mechanism is connected by the 4th automatic dnockout pumps to be carried to the first continuous be quenched with acid quencher entrance
Pure device continuously provides acid quencher, extractant feeding mechanism and extractant entrance by the 5th automatic dnockout pumps be connected with to
First continuous be quenched purifying plant and continuously provide extractant；Alkalinity neutralizes liquid supply unit；And second continuous be quenched purification dress
It sets, there is alkaline neutralizer entrance, first purification entrance and purified product outlet, alkalinity neutralizes liquid supply unit and alkalinity neutralizes
Liquid entrance is connected by the 6th automatic dnockout pumps continuously to provide alkaline neutralizer to the second continuous purifying plant that is quenched, and is just purified
Object outlet is connected with first purification entrance by the 7th automatic dnockout pumps.
Further, above-mentioned saponification unit is continuous enzyme immobilization saponification unit.
Further, above-mentioned continuous enzyme immobilization saponification unit includes the continuous enzyme immobilization soap for saponification to occur
The pH adjusting agent feeding mechanism changed reaction column and be connected with continuous enzyme immobilization saponification column.
Further, above-mentioned continuous synthesis system further includes：Continuous separator, continuous separator are arranged in saponification list
Between member and continuous enzymic catalytic reaction unit.
Further, above-mentioned continuous separator is continuous film separator.
Further, above-mentioned continuous grignard reaction member includes being reacted for carrying out the continuous coil pipe of continuous forms reaction
Device.
Further, above-mentioned continuous enzymic catalytic reaction unit includes continuously stirring reaction for occur enzymic catalytic reaction
Device.
Using the technical solution of the utility model, realized by above-mentioned each unit crucial anti-in non-natural amino acid synthesis
Answer the serialization of step to carry out, thus efficiently utilize the thermal energy in each reaction, the reaction time is also easier to control, therefore
It is possible to prevente effectively from enlarge-effect, so as to preferably control the generation of by-product and impurity, and then improves the pure of reaction
Degree and yield；And since by-product and impurity are reduced, the energy and reagent of purification of products consumption are also reduced, are reduced
Energy consumption, waste discharge and the cost of processing of purification of products.Meanwhile the implementation of continuous reaction so that equipment operation is easy, pacifies
Full property improves, and the working strength of operator reduces, cost of labor also reduces.
Description of the drawings
The accompanying drawings which form a part of this application are used to provide a further understanding of the present invention, this practicality
Novel illustrative embodiments and their description are not constituted improper limits to the present invention for explaining the utility model.
In the accompanying drawings：
Fig. 1 shows the structure diagram of the continuous synthesis system provided according to a kind of exemplary embodiment of the utility model；
And
Fig. 2 shows the structural representations of the continuous synthesis system provided according to a kind of preferred embodiment of the utility model
Figure.
Wherein, above-mentioned attached drawing includes the following drawings label：
10, raw material unit without interruption；11, Grignard Reagent feeding mechanism；12, ester feeding mechanism；111, Grignard Reagent connects
Continuous generating means；112, halogenated alkane feeding mechanism；113, magnesium metal feeding mechanism；
20, continuous grignard reaction member；
30, purifier units are continuously quenched；31, acid quencher feeding mechanism；32, extractant feeding mechanism；33, first connects
It is continuous that purifying plant is quenched；34, alkalinity neutralizes liquid supply unit；35, second purifying plant continuously is quenched；
40, saponification unit；41, continuous enzyme immobilization saponification column；42, pH adjusting agent feeding mechanism；
50, continuous separator；
60, continuous enzymic catalytic reaction unit.
Specific implementation mode
It should be noted that in the absence of conflict, the features in the embodiments and the embodiments of the present application can phase
Mutually combination.The utility model will be described in detail below with reference to the accompanying drawings and embodiments.
As the application background technology is analyzed, in the prior art there is peace in the method for traditional synthesis non-natural amino acid
The full problem that property is poor, yield is low, to solve the above-mentioned problems, this application provides a kind of continuous synthesis of non-natural amino acid systems
System and method for continuously synthesizing.
In a kind of typical embodiment of the application, a kind of continuous synthesis system of non-natural amino acid is provided, such as
Shown in Fig. 1, which includes raw material unit 10 without interruption, continuous grignard reaction member 20, purification continuously is quenched
Unit 30, saponification unit 40 and continuous enzymic catalytic reaction unit 60, continuous grignard reaction member 20 have feed(raw material)inlet and
Product exit, feed(raw material)inlet are connected with raw material unit 10 without interruption；The continuous purifier units 30 that are quenched have object entrance to be purified
It is exported with purified product, object entrance to be purified is connected with product exit；Saponification unit 40 has ester entrance and keto acid product
Outlet, ester entrance are connected with purified product outlet；There is continuous enzymic catalytic reaction unit 60 keto acid product entrance and amino acid to go out
Mouthful, keto acid product entrance is connected with keto acid product outlet.
The continuous synthesis system of the application realizes key reaction in non-natural amino acid synthesis by above-mentioned each unit and walks
Rapid serialization carries out, thus efficiently utilize the thermal energy in each reaction, the reaction time is also easier to control, therefore can be with
Effectively avoid enlarge-effect, so as to preferably control the generation of by-product and impurity, and then improve reaction purity and
Yield；And since by-product and impurity are reduced, the energy and reagent of purification of products consumption also reduce, reduce product
Energy consumption, waste discharge and the cost of processing of purification.Meanwhile the implementation of continuous reaction so that equipment operation simplicity, safety
It improves, the working strength of operator reduces, cost of labor also reduces.
In a kind of preferred embodiment of the application, preferably as shown in Fig. 2, above-mentioned raw materials unit 10 without interruption includes lattice
Family name's agent delivery device 11 and ester feeding mechanism 12, Grignard Reagent feeding mechanism 11 pass through the second automatic dnockout pumps with feed(raw material)inlet
It is connected to carry out Grignard Reagent without interruption to continuous grignard reaction member 20；Ester feeding mechanism 12 passes through third with feed(raw material)inlet
Automatic dnockout pumps are connected to carry out ester without interruption to continuous grignard reaction member 20.
The application supplies Grignard Reagent and ester respectively by the second automatic dnockout pumps and the automatic dnockout pumps of third, using automatic
Dnockout pumps realize precisely feed.
The structure of above-mentioned second automatic dnockout pumps and the automatic dnockout pumps of third and following each automatic dnockout pumps is can
With the pump automatically controlled, wherein not only the pump including being used to provide power further includes the detection device for detecting feeding rate,
For example feeding rate is reacted by detecting raw material weight variation using detection device and be fed according to testing result to adjust
Rate, the structures of above-mentioned automatic dnockout pumps be automatic dnockout pumps in the prior art it is intrinsic, those skilled in the art can
With the specific automatic dnockout pumps with reference to prior art selection suitable for the application, details are not described herein.
In order to further increase the application continuous synthesis system safety, preferably as shown in Fig. 2, above-mentioned Grignard Reagent
Feeding mechanism 11 includes Grignard Reagent continuous generation device 111, halogenated alkane feeding mechanism 112 and magnesium metal feeding mechanism 113,
Grignard Reagent continuous generation device 111 and feed(raw material)inlet are connected by the second automatic dnockout pumps with to continuous grignard reaction member 20
Carry out Grignard Reagent without interruption；Halogenated alkane feeding mechanism 112 is automatic by first with Grignard Reagent continuous generation device 111
Dnockout pumps are connected to carry out halogenated alkane without interruption to Grignard Reagent continuous generation device 111；And magnesium metal feeding mechanism
113 are connected with Grignard Reagent continuous generation device 111 to carry out metal without interruption to Grignard Reagent continuous generation device 111
Magnesium.
The application is connected by the way that Grignard Reagent continuous production device is arranged with continuous forms reaction member so that Grignard Reagent
It is immediately available for subsequent reactions after preparation, avoids the accumulation of a large amount of Grignard Reagent, thereby reduces Grignard Reagent accumulation and causes
Security risk.
Magnesium metal employed in Grignard Reagent preparation well known to those skilled in the art is magnesium powder or magnesium chips, in order to improve gold
Belong to the efficiency of supply and stability of magnesium, preferably above-mentioned magnesium metal feeding mechanism 113 is auger conveyor.
In order to better adapt to Grignard Reagent preparation solid-liquid reaction the characteristics of, preferably above-mentioned Grignard Reagent continuously generates dress
It is continuous-stirring reactor to set 111.Using stirring action in continuous-stirring reactor increase in successive reaction halogenated alkane and
The contact effect of magnesium metal, and then improve reaction efficiency.
In the application another kind preferred embodiment, as shown in Fig. 2, the above-mentioned continuous purifier units 30 that are quenched include acidity
Purifying plant 33 is continuously quenched in quencher feeding mechanism 31, extractant feeding mechanism 32, first, alkalinity neutralizes liquid supply unit 34
With second it is continuous be quenched purifying plant 35, first it is continuous be quenched purifying plant 33 have acid quencher entrance, extractant entrance,
First purification outlet and object entrance to be purified, acid quencher feeding mechanism 31 are beaten with acid quencher entrance by the 4th automatically
Material pump is connected continuously to provide acid quencher, extractant feeding mechanism 32 and extractant to the first continuous purifying plant 33 that is quenched
Entrance is connected by the 5th automatic dnockout pumps continuously to provide extractant to the first continuous purifying plant 33 that is quenched；Second continuously quenches
There is the purifying plant 35 that goes out alkaline neutralizer entrance, first purification entrance and purified product outlet, alkalinity to neutralize liquid supply unit
34 are connected by the 6th automatic dnockout pumps continuously to provide alkali to the second continuous purifying plant 35 that is quenched with alkaline neutralizer entrance
Property neutralizer, the outlet of first purification is connected with first purification entrance by the 7th automatic dnockout pumps.
It is quenched the product system progress acid of continuous grignard reaction member 20 using the above-mentioned first continuous purifying plant 33 that is quenched
It goes out and is carried out at the same time extraction；Then purifying plant 35 continuously is quenched using second to neutralize the acid quencher in first purification
Purification effect is completed in washing, is avoided rotten caused by the long-time accumulation of product.
In order to realize the application continuous synthesis system whole serialization, preferably above-mentioned saponification unit 40 is continuous
Enzyme immobilization saponification unit, preferably continuous enzyme immobilization saponification unit include for the continuous immobilized of enzyme saponification to occur
Saponification column and the pH adjusting agent feeding mechanism 42 being connected with continuous enzyme immobilization saponification column 41.
The realization of batch reaction member may be used in above-mentioned saponification unit 40, for example NaOH solution and reaction is first used to generate
The organic phase reaction of ketone acid, generate corresponding sodium salt and be dissolved in water phase, then liquid separation, then with hydrochloric acid solution that ketone acid sodium is water-soluble
Liquid adjusts pH and ketone acid is extracted into organic phase to faintly acid, then with solvent.The application preferably uses above-mentioned continuous enzyme immobilization soap
Change reaction member to realize being carried out continuously for enzyme saponification so that the continuous synthesis system of the application is able to carry out whole company
Continuous metaplasia production, has further played the advantage of continuous production.In addition, the application further preferably uses continuous enzyme immobilization saponification
Reaction column 41 so that saponification process is more convenient, quick, while saving material, reduces the generation of the three wastes.PH is utilized simultaneously
Value conditioning agent feeding mechanism 42 adjusts the system pH in organic phase and enzyme immobilization reaction process.
Further, preferably as shown in Fig. 2, above-mentioned continuous in order to improve the reaction efficiency of continuous enzymic catalytic reaction unit
Synthesis system further includes continuous separator 50, and continuous separator 50 is arranged in saponification unit 40 and continuous enzymic catalytic reaction list
Between member 60.Continuous purification concentration, and then the company of improving are carried out to the product of enzyme good fortune reaction member using continuous separator 50
The contact effect of reactant, improves reaction efficiency in continuous enzyme-catalyzed reaction.Preferably, above-mentioned continuous separator 50 is to connect
Continuous membrane separator.
For the reactive liquid solution of continuous grignard reaction, preferably above-mentioned continuous grignard reaction member 20 includes continuous for carrying out
The continuous coil reactor of grignard reaction.
Preferably, above-mentioned continuous enzymic catalytic reaction unit 60 includes continuously stirring reaction for occur enzymic catalytic reaction
Device.It is stirred in enzyme-catalyzed reaction using continuous-stirring reactor, improves enzymatic efficiency.
It is another typical in the application in order to make those skilled in the art more easily use above-mentioned continuous synthesis system
In embodiment, a kind of method for continuously synthesizing of non-natural amino acid is provided, which includes：Make Grignard Reagent
Serialization grignard reaction is carried out with ester, obtains ketone acid ester products；Purification processes continuously are quenched to the progress of ketone acid ester products, are carried
Pure ketone acid ester products；So that purification ketone acid ester products is carried out saponification, obtains keto acid product；And keto acid product is made to carry out continuously
Enzymic catalytic reaction obtains non-natural amino acid.
The above-mentioned method for continuously synthesizing of the application realizes the serialization of committed step in non-natural amino acid synthesis
Carry out, thus efficiently utilize the thermal energy in each reaction, the reaction time is also easier to control, therefore it is possible to prevente effectively from puts
Big effect so as to preferably control the generation of by-product and impurity, and then improves the purity and yield of reaction；And due to
By-product and impurity are reduced, thus the energy of purification of products consumption and reagent are also reduced, the energy consumption that reduces purification of products,
The cost of waste discharge and processing.Meanwhile the implementation of continuous reaction so that equipment operation is easy, the safety is improved, operator
Working strength reduce, cost of labor also reduces.
It is preferably above-mentioned in order to give full play to the advantage of serialization grignard reaction in a kind of preferred embodiment of the application
In serialization grignard reaction, the retention time of Grignard Reagent and ester is 5~60min, and reaction temperature is -70~-15 DEG C, preferably
It it is -70~-60 DEG C, more preferable serialization grignard reaction carries out in continuous coil reactor, the molar ratio of ester and Grignard Reagent
It is 0.8~1.5:1.
In order to further increase the application continuous synthesis system safety, preferably above-mentioned method for continuously synthesizing further includes
The continuous process for providing Grignard Reagent, the above-mentioned continuous process for providing Grignard Reagent include：Halogenated alkane is set to be carried out with magnesium continuous
To be continuously available Grignard Reagent, preferably successive reaction carries out in continuous-stirring reactor for reaction, preferably halogenated alkane be containing 3~
The straight chain halogenated alkane of 5 carbon atoms, the branch halogenated alkane containing 3~5 carbon atoms, the halogenated cycloalkanes containing 5~7 carbon atoms
Any one or more in hydrocarbon；The molar ratio of preferably magnesium and halogenated alkane is 1.05~1.3:1.By continuously providing grignard examination
The process of agent avoids the accumulation of a large amount of Grignard Reagent, thereby reduces security risk caused by Grignard Reagent accumulation.
It is above-mentioned continuous purification processes are quenched to include in the application another preferred embodiment：Ketone acid ester products are connected
It is continuous to be delivered to first and continuously be quenched in purifying plant, and to first it is continuous be quenched in purifying plant be continuously added to acid quencher with
Extractant obtains just purified product to carry out that purification is continuously quenched for the first time to ketone acid ester products；First purified product is continuously defeated
It send to second and is continuously quenched in purifying plant, and alkaline neutralizer is continuously added to first to the second continuous be quenched in purifying plant
Acid quencher in purified product carries out neutralization washing, obtains purification ketone acid ester products.It is carried using the above-mentioned first continuous be quenched
Pure device is quenched the ketone acid ester products progress acid of continuous grignard reaction member and is carried out at the same time extraction；Then it continuously quenches using second
The purifying plant that goes out carries out neutralization washing to the acid quencher in first purified product, completes purification effect.
Extractant, acid quencher and alkaline neutralizer for the application can refer to purification institute in the prior art
The tie substance of use, in order to reduce cost for purification and improve refining effect as far as possible, preferably above-mentioned extractant is tetrahydrochysene furan
It mutters, any one or more in 2- methyltetrahydrofurans, ethyl acetate and dichloromethane；Preferred acidic quencher includes acid
Aqueous ammonium chloride solution, acid are any one or more in hydrochloric acid, sulfuric acid and acetic acid, sour mole in preferred acidic quencher
A concentration of 1~3mol/L；The volume ratio of more preferably acidity quencher and ketone acid ester products is 3~8:1；It is preferred that alkaline neutralizer is
Aqueous sodium carbonate, sodium bicarbonate aqueous solution, potassium bicarbonate aqueous solution, sodium hydroxide solution, sodium dihydrogen phosphate, phosphoric acid hydrogen
Any one or more in two sodium solutions, potassium dihydrogen phosphate and dipotassium hydrogen phosphate solution.
In order to realize the application method for continuously synthesizing whole serialization, preferably saponification be continuous enzyme immobilization saponification
Reaction preferably purifies ketone acid ester products and carries out continuous enzyme immobilization saponification in chromatographic column, and the adsorbent of preferably chromatographic column is
One or more in white carbon, diatomite, silica gel, activated carbon, carclazyte, zeolite and magnesium silicate, further preferred adsorbent is
Silica based powders adsorbent (white carbon, diatomite powder, carclazyte, zeolite) and activated carbon.The immobilized enzyme of chromatographic column is selected from
Any one or more in the lipase that porcine pancreatic lipase and any one following strain generate：Dredge that continuous shape is thermophilic invites hyphomycete
(Thermomyces lanuginous), rice black wool mould (Mucor miehei), pseudomonas fluorescens (Pseudomonas
Fluorescens), aspergillus niger (Aspergillusniger), rhizomucor miehei (Rhizopus oryzae), solution fat vacation silk ferment
Female (Candida Rugosa), bulkholderia cepasea (Burkholderia sp.), fold candida (Candida
) and head mold (Rhizopus sp.) and their genetic modification strain rugosa；Further preferred enzyme immobilization is selected from pig pancreas fat
Fat enzyme, thin continuous shape are thermophilic to invite hyphomycete (Thermomyces lanuginous), rice black wool mould (Mucor miehei), fluorescent false single
Born of the same parents bacterium (Pseudomonas fluorescens), aspergillus niger (Aspergillusniger), rhizomucor miehei (Rhizopus
Oryzae), Candida lipolytica (Candida Rugosa), head mold (Rhizopus sp.) and their genetic modification strain
Any one or more in the lipase of generation.To keep saponification process more convenient, quick, while material is saved,
Reduce the generation of the three wastes.
Preferably, the reaction temperature of above-mentioned continuous enzyme immobilization saponification is 25~40 DEG C, preferably 30~35 DEG C, is retained
Time is 2~20h.Utilize the control of above-mentioned temperature and time so that reaction is more convenient, fast, saves material and reduces simultaneously
The generation of the three wastes.
In order to improve the reaction efficiency of continuous enzymic catalytic reaction unit, preferably that keto acid product is carried out continuous enzymatic is anti-
Before answering, method for continuously synthesizing further includes the process that product concentration is carried out to keto acid product, it is preferred to use continuous film point
Continuous concentration processing carried out to keto acid product from device, the separating pressure of further preferred continuous film separator is less than or equal to-
0.08MPa, separation temperature is less than or equal to 45 DEG C, to shorten concentration time.
In another preferred embodiment, above-mentioned continuous enzymic catalytic reaction carries out in continuous-stirring reactor, preferably
Mixing speed is 30~150r/min, and 5~40 DEG C of reaction temperature, retention time is 8~50h；Further preferred mixing speed is
50~70r/min, reaction temperature are 25~35 DEG C, and retention time is 8~16h.To be carried out in continuous enzyme-catalyzed reaction
Stirring improves reactant and contacts effect.The enzyme that ketone acid is converted to amino acid in continuous enzymic catalytic reaction can be from the prior art
In selected, details are not described herein.
Below with reference to embodiment and comparative example, the advantageous effect of the application is further illustrated.
Embodiment 1
The preparation of valine is implemented using continuous reaction system shown in Fig. 2, and reaction route is as follows：
It is without interruption to Grignard Reagent continuous generation device by the first automatic dnockout pumps using halogenated alkane feeding mechanism
Chloroisopropane carries out magnesium chips without interruption, wherein chloro using magnesium metal feeding mechanism to Grignard Reagent continuous generation device
Isopropyl alkane is dissolved in tetrahydrofuran, and the dosage of each substance is shown in Table 1.
Grignard Reagent prepared by Grignard Reagent continuous generation device is carried out with diethy-aceto oxalate in continuous coil reactor
Reaction generates keto ester, and wherein diethy-aceto oxalate is dissolved in tetrahydrofuran, and the specific dosage and reaction condition of each substance are shown in Table
1。
The product system that continuous coil reactor is generated utilizes hydrochloric acid and chlorination in the first continuous be quenched in extraction element
The mixed liquor of ammonium is quenched and 2- methyltetrahydrofurans is used to carry out continuous extraction, and obtained first purified product is continuous second
It is quenched in purifying plant and continuously neutralizes and wash using sodium bicarbonate solution, the ketone acid ester products purified, specific substance
Dosage is shown in Table 1.
The ketone acid ester products of gained purification carry out saponification by continuous enzyme immobilization saponification column and generate ketone acid, reaction
Condition is shown in Table 1, wherein used enzyme is porcine pancreatic lipase, the adsorbent in chromatographic column is white carbon.
The keto acid product that continuous enzyme immobilization saponification column generates carries out film concentration, concentration by continuous film separator
Condition is shown in Table 1.
Ketone acid after concentration carried out in continuous-stirring reactor enzymatic generate valine, wherein the enzyme used for from
Bacillus sphaericus's and with sequence SEQ ID No.1 Phenylalanine dehydrogenase,
MAKQLEKSSKIGNEDVFQKIANHEQIVFCNDPVSGLQAIIAIHDTTLGPALGGTRMYPYKNVDEALEDVLRLSEGMT
YKCAAADIDFGGGKAVIIGDPEKDKSPALFRAFGQFVESLNGRFYTGTDMGTTMDDFVHAQKETNFINGIPEQYGGS
GDSSIPTAQGVIYALKATNQYLFGSDSLSGKTYAIQGLGKVGYKVAEQLLKAGADLFVTDIHENVLNSIKQKSEELG
GSVTIVKSDDIYSVQADIFVPCAMGGIINDKTIPKLKVKAVVGSANNQLKDLRHANVLNEKGILYAPDYIVNAGGLI
QVADELYGPNKERVLLKTKEIYRSLLEIFNQAALDCITTVEAANRKCQKTIEGQQTRNSFFSRGRRPKWNIKE。
Reaction condition is shown in Table 1.
Embodiment 2 to 4
Reaction process is shown in Table 1 with embodiment 1, specific difference.
Table 1
Remarks：Eq in table 1 indicates that molar equivalent, V indicate that (V indicates mL/g to volume, refers to every 1 gram of main material amount institute
With the volume of solvent), N indicates that mol/L, P indicate that purity, Y indicate yield.
Grignard Reagent dosage and the use of magnesium chips are can be seen that according to the data comparison of embodiment 1 and embodiment 2 in table 1
Amount also will produce apparent influence for subsequent reaction；It can be seen that and closing according to embodiment 1 and 4 data comparison of embodiment
On the basis of reason control Grignard Reagent and diethy-aceto oxalate reaction temperature, with the increase of retention time, keto ester purity and receipts
Rate has clear improvement.
Embodiment 5 to 8
Reaction process is shown in Table 2 with embodiment 1, specific difference.
Table 2
It can be found that the reduction of diethy-aceto oxalate and magnesium chips can be according to the data comparison of embodiment 1 and embodiment 6 to 8
Lead to the decline of amino acid purity and yield to a certain degree, this is because caused by raw material reaction ratio imbalance, rather than by
Caused by technique in embodiment.
Embodiment 9 to 14
Reaction process is shown in Table 3 with embodiment 1, specific difference.
Table 3
It is found according to the data comparison of embodiment 1, embodiment 9 and 10, the retention time of the first step is to a certain extent
Extend the purity and yield for being conducive to improve product, still, if when the retention time is more than that subsequent renew of 60min is grown for increasing
The yield of product is added not have apparent synergistic effect.
Embodiment 15
Difference from example 1 is that the mixing speed of continuous enzymic catalytic reaction is 30r/min, reaction temperature 40
DEG C, the purity of retention time 8h, obtained amino acid are 84%, yield 72%.
Embodiment 16
Difference from example 1 is that the mixing speed of continuous enzymic catalytic reaction is 150r/min, reaction temperature 5
DEG C, the purity of retention time 40h, obtained amino acid are 88%, yield 65%.
Embodiment 17
Difference from example 1 is that the mixing speed of continuous enzymic catalytic reaction is 50r/min, reaction temperature 35
DEG C, the purity of retention time 8h, obtained amino acid are 86%, yield 70%.
Embodiment 18
Difference from example 1 is that the mixing speed of continuous enzymic catalytic reaction is 70r/min, reaction temperature 25
DEG C, the purity of retention time 40h, obtained amino acid are 88%, yield 75%.
Embodiment 19
It is with the difference of embodiment 1, continuous concentration processing is not carried out to keto acid product using continuous film separator,
But batch recycles, the purity of final amino acid is 90%, yield 80%.
Embodiment 20
The preparation of 2- methyl phenylglycines, is implemented, reaction route is as follows using continuous reaction system shown in Fig. 2：
It is continuously supplied to Grignard Reagent continuous generation device by the first automatic dnockout pumps using halogenated aromatic feeding mechanism
O-bromotoluene is answered, magnesium chips without interruption is carried out to Grignard Reagent continuous generation device using magnesium metal feeding mechanism, wherein adjacent bromine
Toluene is dissolved in tetrahydrofuran, and the dosage of each substance is shown in Table 4.
Grignard Reagent prepared by Grignard Reagent continuous generation device is carried out with diethy-aceto oxalate in continuous coil reactor
Reaction generates keto ester, and wherein diethy-aceto oxalate is dissolved in tetrahydrofuran, and the specific dosage and reaction condition of each substance are shown in Table
4。
The product system that continuous coil reactor is generated utilizes hydrochloric acid and chlorination in the first continuous be quenched in extraction element
The mixed liquor of ammonium is quenched and 2- methyltetrahydrofurans is used to carry out continuous extraction, and obtained first purified product is continuous second
It is quenched in purifying plant and continuously neutralizes and wash using sodium bicarbonate solution, the ketone acid ester products purified, specific substance
Dosage is shown in Table 4.
The ketone acid ester products of gained purification carry out saponification by continuous enzyme immobilization saponification column and generate ketone acid, reaction
Condition is shown in Table 4, wherein used enzyme is porcine pancreatic lipase, the adsorbent in chromatographic column is white carbon.
The keto acid product that continuous enzyme immobilization saponification column generates carries out film concentration, concentration by continuous film separator
Condition is shown in Table 4.
Ketone acid after concentration carries out enzymatic in continuous-stirring reactor and generates 2- methyl phenylglycines, wherein use
Enzyme be from Bacillus sphaericus's and with sequence SEQ ID No.1 Phenylalanine dehydrogenase,
MAKQLEKSSKIGNEDVFQKIANHEQIVFCNDPVSGLQAIIAIHDTTLGPALGGTRMYPYKNVDEALEDVLRLSEGMT
YKCAAADIDFGGGKAVIIGDPEKDKSPALFRAFGQFVESLNGRFYTGTDMGTTMDDFVHAQKETNFINGIPEQYGGS
GDSSIPTAQGVIYALKATNQYLFGSDSLSGKTYAIQGLGKVGYKVAEQLLKAGADLFVTDIHENVLNSIKQKSEELG
GSVTIVKSDDIYSVQADIFVPCAMGGIINDKTIPKLKVKAVVGSANNQLKDLRHANVLNEKGILYAPDYIVNAGGLI
QVADELYGPNKERVLLKTKEIYRSLLEIFNQAALDCITTVEAANRKCQKTIEGQQTRNSFFSRGRRPKWNIKE。
Reaction condition is shown in Table 4.
Embodiment 21 to 22
Reaction process is shown in Table 4 with embodiment 20, specific difference.
Table 4
Remarks：Eq in table 4 indicates that molar equivalent, V indicate that volume, N indicate that mol/L, P indicate that purity, Y indicate to receive
Rate.
The dosage of magnesium chips and prepared is can be seen that according to the data comparison of embodiment 20 and embodiment 21 in table 4
Grignard reagent concentration will produce apparent influence to the yield of subsequent reactions；It can according to embodiment 20 and 22 data comparison of embodiment
To find out, on the basis of rationally control Grignard Reagent and diethy-aceto oxalate reaction temperature, with the increase of retention time, ketone acid
Ester purity and yield have clear improvement.
Embodiment 23 to 25
Reaction process is shown in Table 5 with embodiment 20, specific difference.
Table 5
The dosage that can be seen that alkali neutralization liquid according to the data comparison of embodiment 23 and embodiment 24 in table 5 ties reaction
Fruit does not influence significantly；It can be seen that according to embodiment 23 and 25 data comparison of embodiment and ensure enough continuous enzyme immobilizations
The saponification time helps to improve final amino acid yield.
Batch reaction is carried out using the prior art, the purity of general gained amino acid is 80~88%, yield is 70~
78%, but purity and yield all decreased significantly after amplifying.
If the successive reaction of the various embodiments described above is persistently carried out or is amplified to kilogram grade, the yield of product with
And purity remains to keep stablizing, therefore the energy of purification of products consumption and reagent are also reduced；And whole process not continuously into
The thermal energy of each reaction process of row can realize comprehensive utilization so that the condition of reaction is easily achieved；The above process does not make simultaneously
With transition-metal catalyst, therefore synthesis cost is relatively low, and Product safety is higher.
It can be seen from the above description that the above embodiments of the present invention achieve the following technical effects：
The continuous synthesis system of the application realizes key reaction in non-natural amino acid synthesis by above-mentioned each unit and walks
Rapid serialization carries out, thus efficiently utilize the thermal energy in each reaction, the reaction time is also easier to control, therefore can be with
Effectively avoid enlarge-effect, so as to preferably control the generation of by-product and impurity, and then improve reaction purity and
Yield；And since by-product and impurity are reduced, the energy and reagent of purification of products consumption also reduce, reduce product
Energy consumption, waste discharge and the cost of processing of purification.Meanwhile the implementation of continuous reaction so that equipment operation simplicity, safety
It improves, the working strength of operator reduces, cost of labor also reduces.
The above-mentioned method for continuously synthesizing of the application realizes the serialization of committed step in non-natural amino acid synthesis
Carry out, thus efficiently utilize the thermal energy in each reaction, the reaction time is also easier to control, therefore it is possible to prevente effectively from puts
Big effect so as to preferably control the generation of by-product and impurity, and then improves the purity and yield of reaction；And due to
By-product and impurity are reduced, thus the energy of purification of products consumption and reagent are also reduced, the energy consumption that reduces purification of products,
The cost of waste discharge and processing.Meanwhile the implementation of continuous reaction so that equipment operation is easy, the safety is improved, operator
Working strength reduce, cost of labor also reduces.
The above descriptions are merely preferred embodiments of the present invention, is not intended to limit the utility model, for this
For the technical staff in field, various modifications and changes may be made to the present invention.It is all in the spirit and principles of the utility model
Within, any modification, equivalent replacement, improvement and so on should be included within the scope of protection of this utility model.
Claims (12)
1. a kind of continuous synthesis system of non-natural amino acid, which is characterized in that including：
Raw material unit without interruption (10)；
Continuous grignard reaction member (20), has feed(raw material)inlet and product exit, the feed(raw material)inlet is continuously supplied with the raw material
Unit (10) is answered to be connected；
Purifier units (30) continuously are quenched, there is object entrance to be purified and purified product to export, the object entrance to be purified and institute
Product exit is stated to be connected；
There is saponification unit (40) ester entrance and keto acid product to export, and the ester entrance exports phase with the purified product
Even；And
Continuous enzymic catalytic reaction unit (60), has keto acid product entrance and acids outlet, the keto acid product entrance and institute
Keto acid product outlet is stated to be connected.
2. continuous synthesis system according to claim 1, which is characterized in that raw material unit without interruption (10) packet
It includes：
Grignard Reagent feeding mechanism (11) is connected by the second automatic dnockout pumps with to the continuous grignard with the feed(raw material)inlet
Reaction member (20) carries out Grignard Reagent without interruption；
Ester feeding mechanism (12) is connected by the automatic dnockout pumps of third with to the continuous grignard reaction list with the feed(raw material)inlet
First (20) carry out ester without interruption.
3. continuous synthesis system according to claim 2, which is characterized in that Grignard Reagent feeding mechanism (11) packet
It includes：
Grignard Reagent continuous generation device (111) is connected by the second automatic dnockout pumps with to the company with the feed(raw material)inlet
Continuous grignard reaction unit (20) carries out Grignard Reagent without interruption；
Halogenated alkane feeding mechanism (112) passes through the first automatic dnockout pumps phase with the Grignard Reagent continuous generation device (111)
Grignard Reagent continuous generation device (111) described in Lian Yixiang carries out halogenated alkane without interruption；And
Magnesium metal feeding mechanism (113) is connected with the Grignard Reagent continuous generation device (111) to connect to the Grignard Reagent
Continuous generating means (111) carry out magnesium metal without interruption.
4. continuous synthesis system according to claim 3, which is characterized in that the magnesium metal feeding mechanism (113) is spiral shell
Revolve conveyer.
5. continuous synthesis system according to claim 3, which is characterized in that the Grignard Reagent continuous generation device
(111) it is continuous-stirring reactor.
6. continuous synthesis system according to claim 1, which is characterized in that the continuous purifier units (30) that are quenched are wrapped
It includes：
Acid quencher feeding mechanism (31)；
Extractant feeding mechanism (32)；
First is continuously quenched purifying plant (33), is exported with acid quencher entrance, extractant entrance, first purification and described
Object entrance to be purified, the acidity quencher feeding mechanism (31) pass through the 4th automatic dnockout pumps with the acid quencher entrance
It is connected continuously to provide acid quencher, the extractant feeding mechanism (32) to the described first continuous purifying plant (33) that is quenched
It is connected by the 5th automatic dnockout pumps with the extractant entrance and is continuously carried so that purifying plant (33) continuously is quenched to described first
For extractant；
Alkalinity neutralizes liquid supply unit (34)；And
Second is continuously quenched purifying plant (35), and there is alkaline neutralizer entrance, first purification entrance and the purified product to go out
Mouthful, the alkalinity neutralizes liquid supply unit (34) and the alkalinity neutralizer entrance is connected by the 6th automatic dnockout pumps with to institute
It states the second continuous purifying plant (35) that is quenched and alkaline neutralizer is continuously provided, the just purification outlet and the just purification enter
Mouth is connected by the 7th automatic dnockout pumps.
7. continuous synthesis system according to claim 1, which is characterized in that the saponification unit (40) is continuous solid
Carry enzyme saponification unit.
8. continuous synthesis system according to claim 7, which is characterized in that the continuous enzyme immobilization saponification unit packet
Include continuous enzyme immobilization saponification column (41) for saponification to occur and with the continuous enzyme immobilization saponification column
(41) connected pH adjusting agent feeding mechanism (42).
9. continuous synthesis system according to claim 1, which is characterized in that the continuous synthesis system further includes：
Continuous separator (50), continuous separator (50) setting are urged in the saponification unit (40) with the continuous enzyme
Between change reaction member (60).
10. continuous synthesis system according to claim 8, which is characterized in that the continuous separator (50) is continuous thin
Membrane separator.
11. continuous synthesis system according to claim 1, which is characterized in that continuous grignard reaction member (20) packet
Include the continuous coil reactor for carrying out continuous forms reaction.
12. continuous synthesis system according to claim 1, which is characterized in that the continuous enzymic catalytic reaction unit (60)
It include the continuous-stirring reactor for enzymic catalytic reaction to occur.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201721722764.7U CN207828318U (en) | 2017-12-12 | 2017-12-12 | A kind of continuous synthesis system of non-natural amino acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201721722764.7U CN207828318U (en) | 2017-12-12 | 2017-12-12 | A kind of continuous synthesis system of non-natural amino acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN207828318U true CN207828318U (en) | 2018-09-07 |
Family
ID=63385991
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201721722764.7U Active CN207828318U (en) | 2017-12-12 | 2017-12-12 | A kind of continuous synthesis system of non-natural amino acid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN207828318U (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108048317A (en) * | 2017-12-12 | 2018-05-18 | 凯莱英医药集团（天津）股份有限公司 | The continuous synthesis system and method for continuously synthesizing of a kind of alpha-non-natural amino acid |
| CN115121184A (en) * | 2022-06-28 | 2022-09-30 | 凯莱英医药集团（天津）股份有限公司 | Vilsmeier reaction continuous reaction device, process and application |
| CN115837258A (en) * | 2023-02-22 | 2023-03-24 | 凯莱英生命科学技术(天津)有限公司 | Continuous preparation device and continuous preparation method of anhydrous peroxyacetic acid |
-
2017
- 2017-12-12 CN CN201721722764.7U patent/CN207828318U/en active Active
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108048317A (en) * | 2017-12-12 | 2018-05-18 | 凯莱英医药集团（天津）股份有限公司 | The continuous synthesis system and method for continuously synthesizing of a kind of alpha-non-natural amino acid |
| CN108048317B (en) * | 2017-12-12 | 2023-08-15 | 凯莱英医药集团（天津）股份有限公司 | Continuous synthesis system and continuous synthesis method of unnatural amino acid |
| CN115121184A (en) * | 2022-06-28 | 2022-09-30 | 凯莱英医药集团（天津）股份有限公司 | Vilsmeier reaction continuous reaction device, process and application |
| CN115121184B (en) * | 2022-06-28 | 2023-10-31 | 凯莱英医药集团（天津）股份有限公司 | Device, process and application of Wilmimaer reaction continuous reaction |
| CN115837258A (en) * | 2023-02-22 | 2023-03-24 | 凯莱英生命科学技术(天津)有限公司 | Continuous preparation device and continuous preparation method of anhydrous peroxyacetic acid |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN207828318U (en) | A kind of continuous synthesis system of non-natural amino acid | |
| CN107217048A (en) | It is a kind of to catalyze and synthesize aminopeptidase of carnosine and its preparation method and application | |
| Kim et al. | Continuous production of gluconic acid and sorbitol from Jerusalem artichoke and glucose using an oxidoreductase of Zymomonas mobilis and inulinase | |
| CN106868030B (en) | Recombinant vector, engineering bacterium containing recombinant vector and application of recombinant vector in production of alpha-ketoglutaric acid | |
| CN105296456A (en) | Glutamic acid decarboxylase mutant with enhanced pH stability and application thereof | |
| EP2430145A2 (en) | Bioreactor process for production of hydrogen from biomass | |
| CN108048317A (en) | The continuous synthesis system and method for continuously synthesizing of a kind of alpha-non-natural amino acid | |
| CN107475320A (en) | The Green production method of L asparatates | |
| CN107779445A (en) | Immobilised lysine decarboxylase, its preparation, 1,5 pentanediamine preparation methods and product | |
| CN106011191B (en) | A kind of method of Whole Cell Biocatalysis production 5- aminovaleric acid | |
| US6828130B2 (en) | Production of gluconate salts | |
| CN103014086A (en) | Method for continuously producing L-ornithine composite salt by enzyme immobilization | |
| CN101130798A (en) | Method for preparing sodium L-aspartate by bio-enzyme | |
| CN104531820A (en) | Method for preparing DL-alanine with fumaric acid as raw material through multi-enzyme coupling | |
| CN112143692B (en) | Lovastatin ester hydrolase recombinant strain, construction method and application | |
| CN110791536B (en) | Biosynthesis method of levodopa | |
| CN102212565A (en) | Preparation method of ultralow-conductivity 30 percent aqueous solution of acrylamide | |
| CN101104862B (en) | Method for synthesizing D-arylglycine by using heterogeneous enzyme to catalytically hydrolyzing 5-arylhydantoin | |
| CN102399845A (en) | VitB12 fermentation production control process based on CO<2> concentration in tail gas | |
| CN115678930A (en) | Preparation method of acrylamide | |
| CN108220351A (en) | A kind of method that biological enzyme prepares L-arginine-α-ketoglutaric acid | |
| CN107083353A (en) | A kind of method that use resting cell produces Aspartame | |
| CN108018321A (en) | The biological synthesis method of l-carnitine | |
| CN102286554A (en) | Method for coproduction of gluconic acid and R(-)-4-cyano-3-hydroxy butanoic acid ethyl ester | |
| CN116926138A (en) | Process for producing acrylamide based on controllable speed of microbiological method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| GR01 | Patent grant | ||
| GR01 | Patent grant |