CN107243307A - Enamine reaction unit - Google Patents
Enamine reaction unit Download PDFInfo
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- CN107243307A CN107243307A CN201710419934.2A CN201710419934A CN107243307A CN 107243307 A CN107243307 A CN 107243307A CN 201710419934 A CN201710419934 A CN 201710419934A CN 107243307 A CN107243307 A CN 107243307A
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- 238000006243 chemical reaction Methods 0.000 title claims abstract description 129
- 150000002081 enamines Chemical class 0.000 title claims abstract description 47
- 239000007795 chemical reaction product Substances 0.000 claims description 31
- 239000000047 product Substances 0.000 claims description 30
- 239000000463 material Substances 0.000 claims description 24
- 238000012546 transfer Methods 0.000 claims description 18
- 230000008676 import Effects 0.000 claims description 17
- 230000005540 biological transmission Effects 0.000 claims description 6
- 230000000977 initiatory effect Effects 0.000 claims description 6
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000004185 ester group Chemical group 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 239000002994 raw material Substances 0.000 abstract description 14
- 230000035484 reaction time Effects 0.000 abstract description 6
- 238000012805 post-processing Methods 0.000 abstract description 5
- 238000012545 processing Methods 0.000 abstract description 5
- 238000000034 method Methods 0.000 description 11
- 230000032258 transport Effects 0.000 description 10
- 150000003934 aromatic aldehydes Chemical class 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 8
- -1 Aromatic aldehyde compound Chemical class 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000000926 separation method Methods 0.000 description 5
- 238000010276 construction Methods 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000010924 continuous production Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000006575 electron-withdrawing group Chemical group 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- BBPNJGRZPSCZBB-UHFFFAOYSA-N siamenol Chemical compound N1C2=CC=C(C)C=C2C2=C1C=C(O)C(CC=C(C)C)=C2 BBPNJGRZPSCZBB-UHFFFAOYSA-N 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WZWIQYMTQZCSKI-UHFFFAOYSA-N 4-cyanobenzaldehyde Chemical class O=CC1=CC=C(C#N)C=C1 WZWIQYMTQZCSKI-UHFFFAOYSA-N 0.000 description 1
- BXRFQSNOROATLV-UHFFFAOYSA-N 4-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=C(C=O)C=C1 BXRFQSNOROATLV-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000006056 electrooxidation reaction Methods 0.000 description 1
- 238000007336 electrophilic substitution reaction Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000009434 installation Methods 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 150000003613 toluenes Chemical class 0.000 description 1
- 238000006276 transfer reaction Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00718—Type of compounds synthesised
- B01J2219/0072—Organic compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a kind of enamine reaction unit.The reaction unit includes reaction member and feed unit, and reaction member includes flow reactor；Feed unit is used for the continuous feeding into flow reactor, and promotes the product continuous discharge in flow reactor.Enamine reaction is carried out by way of reaction raw materials are continuously introduced into reaction member, the serialization of enamine reaction is realized, shortens the reaction time, improve reaction efficiency.On the one hand this continuous reacting device can stop reaction or terminating reaction at any time relative to traditional still reaction device according to actual conditions, post processing also can batch processing or merging treatment as needed, facilitate simple and direct；On the other hand largely solve because temperature is high, the increase of system pressure, the problem of consersion unit is difficult to bear, reduce the degree of danger of reaction.
Description
Technical field
The present invention relates to pharmaceutical synthesis apparatus field, in particular to a kind of enamine reaction unit.
Background technology
Aromatic aldehyde compound is important organic synthesis intermediate, is widely used in biology, medicine, agricultural chemicals, material etc.
Field.Also it is easy to the aldehyde radical of modification because containing, and as the classical organic molecule skeleton for constructing each heterocyclic compounds.For example：
Phenol aromatic aldehyde is important spices and catalyst synthetic intermediate.2- nitro -4- chlorobenzaldehydes are synthesizing anti-AIDS pharmaceuticals
Siamenol important intermediate.4- nitrobenzaldehydes and 4- cyanobenzaldehydes are widely used in synthesis of natural product and activity
Medicine etc..
Tradition prepares the aromatic aldehyde of substituent containing electron, and one of more classical method is reacted for Remier-Tiemann, i.e.,
Fragrant electrophilic substitution reaction occurs in alkaline protonic solvent, but generally there are many deficiencies in the reaction, if desired for denseer
Alkaline solution, excessive chloroform, reaction can only obtain moderate yield product and the limitation such as selectivity of product is poor.1994
Robert Aldred etc. find paraformaldehyde under the catalysis of magnesium chloride can Pyrogentisinic Acid carry out formylated, and obtain good yield
Product, this method is rapid expanded since then.
Comparatively, the aromatic aldehyde compound containing electron withdraw group is prepared more various.It can be divided mainly into (1) enamine oxygen
Change method, i.e., using the toluene derivative containing electron-withdrawing group as raw material, reoxidize after enamine and obtain corresponding aromatic aldehyde.(2) it is straight
Nitrification process is connect, such method is mainly used in aromatic aldehyde of the synthesis containing nitro.The technique not only needs to consume the substantial amounts of concentrated sulfuric acid,
Environment is polluted, while can also produce isomers paranitrobenzaldehyde, the separation and purification to product bring difficulty.(3) directly
Oxidized side chain method and (4) Indirect Electrooxidation etc..
In summary, the synthetic method of electron withdraw group aromatic aldehyde of the prior art has the following disadvantages：(1) tradition system
Standby aromatic aldehyde containing electron-withdrawing group needs to use environment unfriendly, high-risk high poison raw material, and nitrification process uses substantial amounts of concentrated sulfuric acid etc., behaviour
Make dangerous, and corrosion reaction equipment.(2) existing enamine reaction is reacted using glass kettle, will to equipment pressure high-temp resistant
Ask high, the reaction time is long, and efficiency is low, it is impossible to meet a large amount of demand of industrial production.(3) and most enamine reactions steps yield compared with
It is low, it is necessary to which extra additive or catalyst could react.
Therefore, a kind of efficiently simple and direct enamine reaction unit how is developed to improve enamine reaction efficiency, and then is improved
The combined coefficient of electron withdraw group aromatic aldehyde, is always the focus of people's research.
The content of the invention
It is a primary object of the present invention to provide a kind of enamine reaction unit, reacted with solving enamine in the prior art
The problem of efficiency comparison is low.
To achieve these goals, according to an aspect of the invention, there is provided a kind of enamine reaction unit, the enamine
Changing reaction unit includes reaction member and feed unit, and reaction member includes flow reactor；Feed unit is used for continuous
Continuous feeding in reactor, and promote the reaction product continuous discharge in flow reactor.
Further, flow reactor is continuous coil reactor.
Further, enamine reaction unit also includes material mixed cell, and material mixed cell is arranged on feed unit
On the pipeline connected with coil reactor.
Further, enamine reaction unit also includes temperature controlling instruments, and material mixed cell is placed in temperature control with reaction member
In equipment.
Further, enamine reaction unit also includes collection of products and buanch unit, collection of products and buanch unit with
The outlet of coil reactor is connected.
Further, collection of products and buanch unit include collection vessel and Transporting equipment, the import of collection vessel and disk
The outlet of pipe reactor is connected, and the outlet of collection vessel is connected with Transporting equipment.
Further, collection vessel includes the first container and second container that are set up in parallel, the import of the first container and the
The import of two containers is connected with the outlet of coil reactor, the outlet of the first container and the outlet of second container and Transporting equipment
It is connected.
Further, the import of the first container and the import of second container and the outlet of coil reactor pass through collecting
It is connected, collection of products and buanch unit also include the first valve, and the first valve is arranged in collecting.
Further, the outlet of the first container and the outlet of second container are connected with Transporting equipment by transfer conduit,
Collection of products and buanch unit also include the second valve, and the second valve is arranged in transfer conduit.
Further, enamine reaction unit also includes control unit, and the first container and second container are respectively arranged with weight
Amount detector or volume detector, weight tester or volume detector are connected with control unit with to control unit transmission weight
Signal or volume signals, control unit are connected with the first valve, the second valve and Transporting equipment respectively, with according to weight signal
Or the transport path and/or transfer rate of the reaction product of volume signals control reaction member.
Further, collection of products and buanch unit also include power-equipment, and power-equipment is arranged on entering for collection vessel
On the pipeline that mouth is connected with the outlet of coil reactor, enamine reaction unit also includes setting in control unit, collection vessel
Weight tester or volume detector are put, weight tester or volume detector are connected to transmit to control unit with control unit
Weight signal or volume signals, control unit are also connected with power-equipment, collection vessel and Transporting equipment respectively, with basis
Weight signal or volume signals control power-equipment and Transporting equipment are to the transfer rate of reaction product.
Further, control unit is connected with feed unit, to adjust feed unit according to the transfer rate of reaction product
Feeding rate.
Further, enamine reaction unit also includes separative element, and separative element is connected with the outlet of Transporting equipment.
Further, feed unit includes the first delivery pump and conveying N of conveying reaction initiation material, N- dimethyl methyls
Second delivery pump of acid amides dimethylacetal, the first delivery pump and the second delivery pump continuous feeding into flow reactor respectively,
It is the compound shown in formula to react initiation material：
In above-mentioned formula (1), n=0~1, the X of diverse location is each independently N, S, O or C；R1、R2、R3And R4Each solely
On the spot it is selected from H, alkyl, aryl, nitro, halogen, ester group, cyano group or trifluoromethyl, R1、R2、R3And R4It is identical or differ.
Apply the technical scheme of the present invention, enamine is carried out by way of reaction raw materials are continuously introduced into reaction member
Reaction, realizes the serialization of enamine reaction, shortens the reaction time, improve reaction efficiency.This continuous reaction dress
Put relative to traditional still reaction device, on the one hand can stop reaction or terminating reaction, post processing at any time according to actual conditions
Also can batch processing or merging treatment as needed, facilitate simple and direct；On the other hand largely solve because temperature is high, system
Pressure increases, and the problem of consersion unit is difficult to bear, reduces the degree of danger of reaction.
Brief description of the drawings
The Figure of description for constituting the part of the application is used for providing a further understanding of the present invention, and of the invention shows
Meaning property embodiment and its illustrate be used for explain the present invention, do not constitute inappropriate limitation of the present invention.In the accompanying drawings：
Fig. 1 shows the structural representation of the enamine reaction unit in a kind of preferred embodiment according to the present invention.
Above-mentioned accompanying drawing includes the following drawings mark：
10th, reaction member；20th, feed unit；30th, material mixed cell；40th, temperature controlling instruments；50th, collection of products and transfer
Unit；60th, separative element；
51st, collection vessel；52nd, Transporting equipment；R1, the first container；R2, second container；V1, the first valve；V2, the second valve
Door；
P-1, the first delivery pump；P-2, the second delivery pump.
Embodiment
It should be noted that in the case where not conflicting, the feature in embodiment and embodiment in the application can phase
Mutually combination.Describe the present invention in detail below with reference to the accompanying drawings and in conjunction with the embodiments.
The application is described in further detail below in conjunction with specific embodiment, these embodiments are it is not intended that limit this
Apply for scope claimed.
Below in conjunction with the accompanying drawing in the embodiment of the present invention, the technical scheme in the embodiment of the present invention is carried out clear, complete
Site preparation is described, it is clear that described embodiment is only a part of embodiment of the invention, rather than whole embodiments.Below
Description only actually at least one exemplary embodiment is illustrative, is never used as to the present invention and its application or makes
Any limitation.Based on the embodiment in the present invention, those of ordinary skill in the art are not making creative work premise
Lower obtained every other embodiment, belongs to the scope of protection of the invention.
For the ease of description, space relative terms can be used herein, such as " ... on ", " ... top ",
" ... upper surface ", " above " etc., for describing such as a device shown in the figure or feature and other devices or spy
The spatial relation levied.It should be appreciated that space relative terms are intended to comprising the orientation except device described in figure
Outside different azimuth in use or operation.If for example, the device in accompanying drawing is squeezed, be described as " in other devices
It will be positioned as " under other devices or construction after the device of part or construction top " or " on other devices or construction "
Side " or " under other devices or construction ".Thus, exemplary term " ... top " can include " ... top " and
" in ... lower section " two kinds of orientation.The device can also other different modes positioning (being rotated by 90 ° or in other orientation), and
And respective explanations are made to the relative description in space used herein above.
In the description of the invention, it is to be understood that the noun of locality such as " forward and backward, upper and lower, left and right ", " laterally, vertical,
Vertically, orientation or position relationship indicated by level " and " top, bottom " etc. are normally based on orientation shown in the drawings or position and closed
System, is for only for ease of the description present invention and simplifies description, in the case where not making opposite explanation, these nouns of locality are not indicated that
There must be specific orientation or with specific azimuth configuration and operation with the device or element for implying meaning, therefore can not manage
Solve as limiting the scope of the invention；The noun of locality " inside and outside " refers to relative to inside and outside each part profile in itself.
As background technology is previously mentioned, the synthetic method of aldehyde compound in the prior art, especially containing electron withdraw group
The synthetic method of aromatic aldehyde compound there is the low defect of reaction efficiency, to improve this situation, in a kind of allusion quotation of the application
There is provided a kind of enamine reaction unit in the embodiment of type, as shown in figure 1, the enamine reaction unit includes reaction list
Member 10 and feed unit 20, reaction member 10 include flow reactor；Feed unit 20 is used for continuous into flow reactor
Feed, and promote the product continuous discharge in flow reactor.
Above-mentioned enamine reaction unit, it is anti-by way of reaction raw materials are continuously introduced into reaction member to carry out enamine
Should, the serialization of enamine reaction is realized, the reaction time is shortened, improves reaction efficiency.This continuous reacting device
Relative to traditional still reaction device, on the one hand reaction or terminating reaction, post processing can be stopped at any time according to actual conditions
Can batch processing or merging treatment as needed, facilitate simple and direct；On the other hand largely solve because temperature is high, system pressure
Strong increase, the problem of consersion unit is difficult to bear, reduces the degree of danger of reaction.
Above-mentioned flow reactor is excellent in this application using that can realize the reactor of successive reaction in the prior art
Choosing uses continuous coil reactor.
Reaction raw materials are continuously fed and promoted the side of product continuous discharge by above-mentioned feed unit 20 into reactor
Formula can have a variety of, any to realize that continuous feeding and the mode of reaction product discharging are applied to the application.Preferably, on
Stating reaction unit also includes material mixed cell 30, and material mixed cell 30 is arranged on feed unit 20 and connected with coil reactor
Pipeline on.Mixed cell is set to be easy to individually convey material between feed unit 20 and reaction member 10, then in material
Progress enamine reaction in reactor is passed through after being well mixed in mixed cell 30 again.This setup is relatively more square in the application
Just, it is well mixed without independent, then individually conveying.
Above-mentioned enamine reaction unit, the temperature according to needed for reaction rationally sets the reaction temperature of reaction member 10.It is preferred that
Ground, above-mentioned reaction unit also includes temperature controlling instruments 40, and material mixed cell 30 is placed in temperature controlling instruments 40 with reaction member 10.Tool
The temperature controlling instruments 40 of body can be insulation jacket either oil bath pan etc..
Above-mentioned enamine reaction unit also includes collection of products and buanch unit 50, collection of products and buanch unit 50 and disk
The outlet of pipe reactor is connected.Collection of products and buanch unit 50 continuously can continuously receive the reaction product of coil reactor
Collect and remove.
Above-mentioned collection of products and buanch unit 50 implement form and can have a variety of, in a kind of preferred reality of the application
Apply in example, collection of products and buanch unit 50 include collection vessel 51 and Transporting equipment 52, the import of collection vessel 51 and coil pipe
The outlet of reactor is connected, and the outlet of collection vessel 51 is connected with Transporting equipment 52.Collection vessel 51 is less than before may be used
Continuously to collect, and it can start Transporting equipment 52 after expiring and continuously be transported.Can also according to actual needs, in collection vessel
51 less than before, such as Transporting equipment 52 can be started by being collected into after predetermined.
In a kind of preferred embodiment, above-mentioned collection vessel 51 includes the first container R1 and second container being set up in parallel
R2, the first container R1 import and second container R2 import are connected with the outlet of coil reactor, and the first container R1's goes out
The outlet of mouth and second container R2 is connected with Transporting equipment 52., both can be simultaneously by setting two containers to be collected
To material collection and transport, material can also be collected and be transported in turn as needed, specific collection and transport form can
To carry out reasonable selection and setting according to actual needs.
Preferably, the import and the import of second container and the outlet of coil reactor of above-mentioned first container pass through collecting pipe
Road is connected, and collection of products and buanch unit 50 also include the first valve V1, and the first valve V1 is arranged in collecting.
It is further preferred that the outlet of above-mentioned first container and the outlet of second container pass through transfer conduit with Transporting equipment
It is connected, collection of products and buanch unit 50 also include the second valve V2, the second valve V2 is arranged in transfer conduit.
In above preferred embodiment, by being set on the pipeline that two different collection vessels 51 are connected with coil reactor
Valve is put, the number of the material according to two container collections be easy to, switches R2 pairs of the first container R1 and second container for greater flexibility
The collection of reaction product.
Similarly, by setting valve on the pipeline that collection vessel 51 is connected with Transporting equipment 52, it is easy to basis
The number of the material of two container collections, switches the transport of the first container R1 and second container R2 to reaction product for greater flexibility.
Above-mentioned first valve V1 and the second valve V2 specific species are simultaneously not particularly limited, as long as can realize to corresponding
Collection vessel 51 is turned on and off.In actual production, the first valve V1 first opens the first container R1 (while closing
Close second container R2), after treating that the first container R1 is full of, the first valve V1 closes the first container R1 and (held while opening second
Device R2), the second valve V2 connect the first container R1 connected with follow-up Transporting equipment 52 (simultaneously close off second container R2 and fortune
Send the connection of equipment 52).And after second container R2 is full of, the second valve V2 connection second container R2 and Transporting equipment 52
(connection for simultaneously closing off the first container R1 and Transporting equipment 52).
In a kind of preferred embodiment, enamine reaction unit also includes control unit, the first container and second container
It is respectively arranged with weight tester or volume detector, weight tester or volume detector are connected with control unit with to control
Unit transmission weight signal or volume signals, control unit are connected with the first valve, the second valve and Transporting equipment respectively, with
According to weight signal or the transport path and/or transfer rate of the reaction product of volume signals control reaction member.
Unless specifically stated otherwise, the part and positioned opposite, the digital table of step otherwise illustrated in these embodiments
Do not limited the scope of the invention up to formula and numerical value.Simultaneously, it should be appreciated that for the ease of description, each portion shown in accompanying drawing
The size divided not is to be drawn according to actual proportionate relationship.For technology, side known to person of ordinary skill in the relevant
Method and equipment may be not discussed in detail, but in the appropriate case, the technology, method and apparatus should be considered as authorizing explanation
A part for book.In shown here and discussion all examples, any occurrence should be construed as merely exemplary, and
Not by way of limitation.Therefore, the other examples of exemplary embodiment can have different values.It should be noted that：Similar label
Similar terms is represented in following accompanying drawing with letter, therefore, once it is defined in a certain Xiang Yi accompanying drawing, then subsequent attached
It need not be further discussed in figure.
In above preferred embodiment, the annexation between unit that control unit is connected to each, equipment, part, root
According to the control flow of needs of production design automation, to realize that the reaction product to reaction member 10 uses different transport roads
Footpath is conveyed.It is also possible to according to feeding rate and the fortune of the reaction product of reaction member 10 of the feed unit 20 to raw material
Transmission rate carries out Auto-matching, so as to realize the continuous production of enamine reaction.
Preferably, with the discharge of reaction product, under the control of the control unit, the first container R1 of the first valve V1 directions
Open (collection for simultaneously closing off second container R2), the second valve V2 is closed, reaction product enters the first container R1 and carried out continuously
Collect；After treating that the first container R1 is received completely, the first valve V1 is opened towards second container R2 and (is simultaneously closed off the first container R1 receipts
Collection), reaction product proceeds continuous collection into second container R2；At the same time, the second valve V2 is opened, the first container R1
In reaction product pass through Transporting equipment 52 continuously transport.Under the control of the control unit, the first container R1 transport speed with
Second container R2 collection rate is identical, and then can continuously transport second container R2 collections after the first container R1 transports terminate
Reaction product, and the first container R1 then continuous collecting reaction products and so on, realize being carried out continuously and producing for reaction
The continuous discharge of thing.
It is highly preferred that control unit can by the weight of the first container R1 and/or second container R2 reaction products or
Volume monitors its collection situation, and then the first valve of feedback control V1 opening direction.
In another preferred embodiment, above-mentioned collection of products and buanch unit 50 also include power-equipment, and power is set
Standby to be arranged on the pipeline that the import of collection vessel 51 is connected with the outlet of coil reactor, enamine reaction unit also includes
Control unit, collection vessel sets weight tester or volume detector, weight tester or volume detector and control unit
Be connected with to control unit transmission weight signal or volume signals, control unit also respectively with power-equipment, collection vessel and
Transporting equipment is connected, to control the conveying of power-equipment and Transporting equipment to reaction product according to weight signal or volume signals
Speed.
In above preferred embodiment, by setting weight detecting itself or volume detector on collection vessel, and this is heavy
Amount detector or volume detector are connected with control unit, by the weight signal or volume signals of collection vessel reaction product
Control unit is sent in real time, so that control unit is according to the weight signal or volume signals, it is dynamic that real-time monitoring is communicated therewith
Power equipment and Transporting equipment realize the continuous collection of reaction product and continuous transfer phase to the transfer rate of reaction product
Match somebody with somebody.
In another preferred embodiment, above-mentioned control unit is also connected with feed unit 20, with according to reaction product
Transfer rate adjust feed unit feeding rate.
By the way that control unit is connected with feed unit 20, in continuous collecting reaction product and continuous transfer reaction product
On the basis of, it furthermore achieved that and match with continuous feeding.That is the enamine reaction unit of the application can either automatic precision
Charging rate is controlled and adjusted accurately, collection and the transfer speed of automatic reasonable adjusting reaction product can be also realized, realize
The automation of continuous production.
Above-mentioned reaction unit to reaction product after transporting, according to the difference of subsequent treatment, can also include different
Processing unit.In a kind of preferred embodiment, above-mentioned reaction unit also includes solid-liquid separation unit 60, solid-liquid separation unit 60
Outlet with Transporting equipment 52 is connected.By being connected with solid-liquid separation unit 60, solid product is obtained, target alkene is realized
The purifying of aminate.
In above-mentioned reaction unit, the specific feed form of feed unit 20 is not limited, and can be that every kind of raw material is supplied respectively
Expect or unify feed again after being first well mixed.In the application, preferably feed unit 20 includes conveying reaction initiation material
The first delivery pump P-1 and convey DMF dimethylacetal the second delivery pump P-2, the first delivery pump P-
1 and the second delivery pump P-2 continuous feeding into coil reactor respectively, reaction initiation material is the compound shown in formula (1)：
In above-mentioned formula (1), n=0~1, the X of diverse location is each independently N, S, O or C；R1、R2、R3And R4Each solely
On the spot it is selected from H, alkyl, aryl, nitro, halogen, ester group, cyano group or trifluoromethyl, R1、R2、R3And R4It is identical or differ.
In above-mentioned enamine reaction unit, the feed mode of this raw material is easy to the installation and operation of equipment, and can
Realize that serialization, the scale of the aromatic aldehyde containing electron withdraw group are combined to.
It should be noted that term used herein above is merely to describe embodiment, and be not intended to restricted root
According to the illustrative embodiments of the application.As used herein, unless the context clearly indicates otherwise, otherwise singulative
It is also intended to include plural form, additionally, it should be understood that, when in this manual using term "comprising" and/or " bag
Include " when, it indicates existing characteristics, step, operation, device, component and/or combinations thereof.
Beneficial effects of the present invention are further illustrated by the following examples：
Embodiment
(1) specification of equipment：250mL coil pipes, diameter 6mm, flow velocity is 2.0g/min；Residence time is 120min, the outlet back of the body
Pressure valve 1.5 ± 0.5MPa of back pressure, circulates oil bath, 50mL plunger pumps, 5000g balances, 1.0L charging bottles.
(2) reaction condition：
Preparation raw material mixed liquor：2- nitrotoleunes 13.7g, 10vol DMF and 41.1g (3.0g/ are added into dnockout bottle
G) DMF dimethylacetal, shakes up stand-by.
Bath temperature outside coil reactor is risen to 170~175 DEG C, DMF is pumped into coil reactor, system back pressure is stable
Untill, raw material mixed liquor is connected on pump 1, retention time 120min is set, charging rate 1.90g/min is to coil reactor
Middle dnockout.During the system for exporting out from coil reactor is directly entered receiving bottle.Raw material mixed liquor is all pumped into after reactor,
Keep flow velocity constant, reaction system is replaced with the DMF equivalent to two times of coil reactor volumes.Pump and reaction are closed after being replaced
Outer bath oil bath.Post processing, 0~10 DEG C of temperature control is slowly added to 10vol purified waters, insulated and stirred 0.5h, production into system under stirring
Product are separated out, and suction filtration obtains red-brown powder shape solid 18.2g, yield 95%.
As can be seen from the above description, the above embodiments of the present invention realize following technique effect：(1) first
Realize using serialization equipment, the first benzene and its derivative of electron withdraw group is contained as raw material using ortho position, it is anti-by serialization
Should, occur enamine reaction with DMF dimethylacetal (DMF-DMA).(2) the application art scheme first step alkene
Amination step, the reaction time is short, and product yield is high, and post-processing operation is simple, and total synthetic route cost is low, environmentally friendly, is each
The aromatic aldehyde synthesis of class substitution efficiently synthesizes approach there is provided one.(3) the application synthesizer highly versatile, for containing richness
The synthesis of the aryl or miscellaneous aromatic aldehyde of electronics or electron deficient substituent, can obtain higher yield, with good functional group
Compatibility.(4) use of serialization equipment, has saved human cost, is beneficial to industry's enlarging production.(5) serialization equipment
Use, largely solve because temperature is high, the increase of system pressure, the problem of consersion unit is difficult to bear, the dangerous journey of reaction
Degree reduction.(6) the relatively conventional reaction of the continuous reaction, can stop reaction or terminating reaction, rear place at any time according to actual conditions
Reason also can batch processing or merging treatment as needed, facilitate simple and direct.
The reaction of the application is carried out at high temperature under high pressure, using the reaction unit of the application raw material accumulation can be avoided to bring
Risk, while greatly shortening the reaction time；Equipment operation is easy, and continuous feed continuously goes out product, reduces personnel cost, work
Labor intensity is low, safe, and automaticity is high.
In a preferred embodiment, the reaction unit of the application is connected successive reaction and continuous separation, Jin Ershi
Show the continuous and automatic synthesis of fragrant enamine compound, be adapted to the synthesis of mass enamine compound.
The preferred embodiments of the present invention are the foregoing is only, are not intended to limit the invention, for the skill of this area
For art personnel, the present invention can have various modifications and variations.Within the spirit and principles of the invention, that is made any repaiies
Change, equivalent substitution, improvement etc., should be included in the scope of the protection.
Claims (14)
1. a kind of enamine reaction unit, it is characterised in that the enamine reaction unit includes：
Reaction member (10), the reaction member (10) includes flow reactor；And
Feed unit (20), the feed unit (20) is used for the continuous feeding into the flow reactor, and promotes the company
Reaction product continuous discharge in continuous reactor.
2. reaction unit according to claim 1, it is characterised in that the flow reactor is continuous coil reactor.
3. reaction unit according to claim 2, it is characterised in that the enamine reaction unit also includes material and mixed
Unit (30), the material mixed cell (30) is arranged on the pipeline that the feed unit (20) is connected with the coil reactor
On.
4. reaction unit according to claim 3, it is characterised in that the enamine reaction unit also includes temperature controlling instruments
(40), the material mixed cell (30) is placed in the temperature controlling instruments (40) with the reaction member (10).
5. reaction unit according to claim 4, it is characterised in that the enamine reaction unit also includes collection of products
And buanch unit (50), the collection of products and buanch unit (50) are connected with the outlet of the coil reactor.
6. reaction unit according to claim 5, it is characterised in that the collection of products and buanch unit (50) include：
Collection vessel (51), the import of the collection vessel (51) is connected with the outlet of the coil reactor；And
Transporting equipment (52), the outlet of the collection vessel (51) is connected with the Transporting equipment (52).
7. reaction unit according to claim 6, it is characterised in that the collection vessel (51) include being set up in parallel the
One container (R1) and second container (R2), the import of first container (R1) and the import of the second container (R2) with it is described
The outlet of coil reactor is connected, the outlet of first container (R1) and the outlet of the second container (R2) and the fortune
Equipment (52) is sent to be connected.
8. reaction unit according to claim 7, it is characterised in that the import and described second of first container (R1)
The import of container (R2) is connected with the outlet of the coil reactor by collecting, the collection of products and buanch unit
(50) also include：
First valve (V1), first valve (V1) is arranged in the collecting.
9. reaction unit according to claim 8, it is characterised in that the outlet and described second of first container (R1)
The outlet of container (R2) is connected with the Transporting equipment (52) by transfer conduit, the collection of products and buanch unit (50)
Also include：
Second valve (V2), second valve (V2) is arranged in the transfer conduit.
10. reaction unit according to claim 9, it is characterised in that it is single that the enamine reaction unit also includes control
Member, first container (R1) and the second container (R2) are respectively arranged with weight tester or volume detector, described heavy
Amount detector or the volume detector are connected with described control unit with to described control unit transmission weight signal or volume
Signal, described control unit respectively with first valve (V1), second valve (V2) and the Transporting equipment (52)
Be connected, with the transport path of reaction product that the reaction member (10) is controlled according to the weight signal or volume signals and/
Or transfer rate.
11. reaction unit according to claim 6, it is characterised in that the collection of products and buanch unit (50) are also wrapped
Power-equipment is included, the import that the power-equipment is arranged on the collection vessel (51) is connected with the outlet of the coil reactor
On logical pipeline, the enamine reaction unit also includes setting weight tester in control unit, the collection vessel (51)
Or volume detector, the weight tester or the volume detector are connected with described control unit with to described control unit
Transmission weight signal or volume signals, described control unit are also connected with the power-equipment and the Transporting equipment (52) respectively
It is logical, to control the power-equipment and the Transporting equipment (52) to reaction product according to the weight signal or volume signals
Transfer rate.
12. the reaction unit according to claim 10 or 11, it is characterised in that described control unit and the feed unit
(20) it is connected, to adjust the feeding rate of the feed unit (20) according to the transfer rate of the reaction product.
13. the reaction unit according to any one of claim 1 to 11, it is characterised in that the enamine reaction unit
Also include separative element (60), the separative element (60) is connected with the outlet of the Transporting equipment (52).
14. the reaction unit according to any one of claim 1 to 11, it is characterised in that feed unit (20) bag
Include：
The first delivery pump (P-1) of conveying reaction initiation material and the second of conveying N,N-dimethylformamide dimethylacetal
Delivery pump (P-2), first delivery pump (P-1) and the second delivery pump (P-2) are continuously supplied into the flow reactor respectively
Material, the reaction initiation material is the compound shown in formula (1)：
In above-mentioned formula (1), n=0~1, the X of diverse location is each independently N, S, O or C；R1、R2、R3And R4Independently of one another
Selected from H, alkyl, aryl, nitro, halogen, ester group, cyano group or trifluoromethyl, the R1、R2、R3And R4It is identical or differ.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109761741A (en) * | 2019-02-18 | 2019-05-17 | 吉林凯莱英制药有限公司 | Prepare the device and method of difluoro cyclopropanes compound |
| CN109794215A (en) * | 2019-02-18 | 2019-05-24 | 凯莱英医药集团（天津）股份有限公司 | The method of continuous device and continuous chlorination pyridone substance for chlorination pyridone substance |
| CN110372462A (en) * | 2019-08-06 | 2019-10-25 | 吉林凯莱英医药化学有限公司 | It is continuously synthesizing to-purifies integrated device and the continuous reaction system containing it |
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