CN108892616B - Continuous device for preparing benzaldehyde intermediate and application thereof - Google Patents
Continuous device for preparing benzaldehyde intermediate and application thereof Download PDFInfo
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- CN108892616B CN108892616B CN201811015497.9A CN201811015497A CN108892616B CN 108892616 B CN108892616 B CN 108892616B CN 201811015497 A CN201811015497 A CN 201811015497A CN 108892616 B CN108892616 B CN 108892616B
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- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 title claims abstract description 58
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 title claims abstract description 29
- 238000006243 chemical reaction Methods 0.000 claims abstract description 114
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 80
- 238000006138 lithiation reaction Methods 0.000 claims abstract description 69
- 239000002994 raw material Substances 0.000 claims abstract description 62
- 238000006170 formylation reaction Methods 0.000 claims abstract description 59
- 230000022244 formylation Effects 0.000 claims abstract description 35
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims abstract description 20
- 229910052744 lithium Inorganic materials 0.000 claims abstract description 20
- 238000007599 discharging Methods 0.000 claims abstract description 15
- 238000010791 quenching Methods 0.000 claims description 44
- 230000000171 quenching effect Effects 0.000 claims description 44
- 238000001816 cooling Methods 0.000 claims description 39
- 239000007788 liquid Substances 0.000 claims description 37
- 239000003795 chemical substances by application Substances 0.000 claims description 35
- 125000001979 organolithium group Chemical group 0.000 claims description 34
- 239000000543 intermediate Substances 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 21
- 230000035484 reaction time Effects 0.000 claims description 17
- 238000004891 communication Methods 0.000 claims description 6
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical group [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 5
- -1 2-bromo-4-fluorobenzaldehyde tert-butyl tetrahydrofuran Chemical compound 0.000 claims 1
- 150000001299 aldehydes Chemical group 0.000 claims 1
- 230000009286 beneficial effect Effects 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 8
- 238000005265 energy consumption Methods 0.000 abstract description 5
- 239000000047 product Substances 0.000 description 27
- 230000008569 process Effects 0.000 description 13
- 238000007086 side reaction Methods 0.000 description 10
- 230000000694 effects Effects 0.000 description 8
- 238000005112 continuous flow technique Methods 0.000 description 6
- 230000002349 favourable effect Effects 0.000 description 4
- 239000011261 inert gas Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000001308 synthesis method Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000003172 aldehyde group Chemical group 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 238000007037 hydroformylation reaction Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000003321 amplification Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 229910003002 lithium salt Inorganic materials 0.000 description 2
- 159000000002 lithium salts Chemical class 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- OPZDXMCOWFPQPE-UHFFFAOYSA-N 2-bromo-4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C(Br)=C1 OPZDXMCOWFPQPE-UHFFFAOYSA-N 0.000 description 1
- JSGJYMFTXDVDNN-UHFFFAOYSA-N 2-tert-butyloxolane Chemical compound CC(C)(C)C1CCCO1 JSGJYMFTXDVDNN-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000010923 batch production Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000010924 continuous production Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/313—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of doubly bound oxygen containing functional groups, e.g. carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
- C07F1/02—Lithium compounds
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a continuous device for preparing a benzaldehyde intermediate and application thereof. The continuous device comprises a continuous lithiation reaction device and a continuous formylation device. The continuous lithiation reaction device is provided with a first feed inlet and a first discharge outlet, wherein the first feed inlet is used for adding reaction raw materials and organic lithium reagents, and the first discharge outlet is used for continuously discharging a product system of the continuous lithiation reaction; the continuous formylation device is provided with a second feed inlet, a formylation reagent inlet and a second discharge outlet, wherein the second feed inlet is communicated with the first discharge outlet, so that a product system of the continuous lithiation reaction is continuously conveyed into the continuous formylation device, the formylation reagent inlet is used for adding the formylation reagent, and the second discharge outlet is used for continuously discharging the product system of the continuous formylation reaction. The device is beneficial to improving the reaction selectivity, reducing the energy consumption and facilitating the industrialized production.
Description
Technical Field
The invention relates to the field of synthesis of medical intermediates, in particular to a continuous device for preparing benzaldehyde intermediates and application thereof.
Background
Benzaldehyde intermediates are a common and very important class of pharmaceutical intermediates. The synthesis method mainly comprises a toluene oxidation method, a Wilsmeier reaction formylation method of an aromatic ring, a direct carbonyl inserting method on a benzene ring, a low-temperature lithiation aldehyde group feeding method and the like. The low-temperature lithiation aldehyde group is a very classical synthesis method, and can form very good complementation with other synthesis methods.
Using a traditional batch reaction process, the low temperature lithiation hydroformylation process is as follows: the raw materials and the solvent are added into a reactor and stirred and dissolved under the protection of nitrogen. Then the raw material solution is cooled to-78 ℃ under the protection of inert gas. And simultaneously controlling the temperature at minus 78 ℃, and dropwise adding the lithium diisopropylamide solution into the reaction system. After the dripping is finished, the reaction system is stirred for 0.5 to 1.5 hours under heat preservation. The temperature of the reaction system is continuously controlled to be minus 78 ℃, and N, N-dimethylformamide is added dropwise into the reaction system. After the dripping is finished, the system is stirred for 10min under heat preservation. Then the system was quenched by dropwise addition of acid solution.
When carrying out low temperature lithiation reactions using conventional batch reaction processes, the following disadvantages generally exist:
1. Very low reaction temperature is needed, energy consumption is high, and cost is high. In low temperature lithiation processes for batch reactions as disclosed in the prior art, the reaction temperature typically needs to be controlled below-70 ℃.
2. The batch reaction is a full mixed flow reaction mode, and the high-activity lithium salt intermediate generated in the reaction process can be uniformly or approximately uniformly dispersed in a reaction system, so that the high-activity lithium salt intermediate is very unfavorable for substrates containing active groups in the structure and reacts with the active groups in the structure, the selectivity of the reaction is poor, and the main reaction yield and the purity of the system are very low.
3. The amplifying effect is obvious, and the process is not easy to amplify. The aldehyde group reaction is carried out by low-temperature lithiation, and the heat release of the reaction is large. The use of batch reactors with low mass and heat transfer efficiency for amplification can lead to severe amplification effects. Thereby greatly reducing the purity and the yield. And after the process is amplified, in order to control the temperature of the system, the dropping rate of the materials is usually controlled very slowly, which not only reduces the production efficiency, but also increases the risk of deterioration of each material in the reaction system.
Disclosure of Invention
The invention mainly aims to provide a continuous device for preparing a benzaldehyde intermediate and application thereof, so as to solve the problems of severe reaction conditions and poor reaction selectivity of the existing batch preparation method of benzaldehyde.
In order to achieve the above object, according to one aspect of the present invention, there is provided a continuous apparatus for preparing a benzaldehyde-based intermediate, the continuous apparatus comprising a continuous lithiation reaction apparatus and a continuous formylation apparatus. The continuous lithiation reaction device is provided with a first feed inlet and a first discharge outlet, wherein the first feed inlet is used for adding reaction raw materials and organic lithium reagents, and the first discharge outlet is used for continuously discharging a product system of the continuous lithiation reaction; the continuous formylation device is provided with a second feed inlet, a formylation reagent inlet and a second discharge outlet, wherein the second feed inlet is communicated with the first discharge outlet, so that a product system of the continuous lithiation reaction is continuously conveyed into the continuous formylation device, the formylation reagent inlet is used for adding the formylation reagent, and the second discharge outlet is used for continuously discharging the product system of the continuous formylation reaction.
Further, the continuous quenching device further comprises a continuous quenching device, wherein the continuous quenching device is provided with a third feed inlet and a quenching agent inlet, the third feed inlet is communicated with the second discharge outlet and is used for continuously conveying a product system of the continuous formylation reaction to the continuous quenching device, and the quenching agent inlet is used for adding the quenching agent.
Further, the continuous lithiation reaction apparatus, the continuous formylation apparatus, and the continuous quenching apparatus are each independently selected from a continuous coil reaction apparatus or a continuous stirred tank reaction apparatus.
Further, the serialization device further comprises a first precooling device, a second precooling device and a first jacket external bath temperature control device, wherein the first precooling device is provided with a reaction raw material inlet and a precooling raw material liquid outlet; the second precooling device is provided with an organolithium reagent inlet and a precooled organolithium reagent outlet; the first jacket external bath temperature control device is used for controlling the temperatures of the first pre-cooling device and the second pre-cooling device; the precooling raw material liquid outlet and the precooling organic lithium reagent outlet are communicated with the first feed inlet, so that the precooling raw material liquid and the precooling organic lithium reagent are continuously conveyed to the continuous lithiation reaction device.
Further, the serialization apparatus further includes a formylating agent supply device and a first transfer pump. The formylating reagent supply device is provided with a formylating reagent supply port which is communicated with the formylating reagent inlet and is used for continuously conveying the formylating reagent into the continuous formylating device; the first transfer pump is disposed in the flow path between the formylating agent supply port and the formylating agent inlet port.
Further, the serialization device also comprises a third precooling device and a second jacket external bath temperature control device. The third precooling device is arranged at the downstream of the first conveying pump along the flow direction of the formylating agent; and the second jacket external bath temperature control device is used for controlling the temperature in the third precooling device.
Further, the continuous device further comprises a raw material liquid supply device and a second conveying pump, wherein the raw material liquid supply device is provided with a raw material liquid supply port, and the raw material liquid supply port is communicated with the reaction raw material inlet and is used for continuously conveying the raw material liquid into the first precooling device; the second transfer pump is provided in a flow path between the raw material liquid supply port and the reaction raw material inlet port.
Further, the serialization device further comprises an organic lithium reagent supply device and a third delivery pump, the organic lithium reagent supply device is provided with an organic lithium reagent supply port, the organic lithium reagent supply port is communicated with the organic lithium reagent inlet, and the organic lithium reagent supply device is used for continuously delivering the organic lithium reagent into the second precooling device; the third transfer pump is provided in a flow path between the organolithium reagent supply port and the organolithium reagent inlet port.
Further, the serialization device further comprises a quencher supply device and a fourth conveying device, wherein the quencher supply device is provided with a quencher supply port which is communicated with the quencher inlet and is used for continuously conveying the quencher into the continuous quenching device; the fourth conveying device is arranged on a flow path between the quencher supply port and the quencher inlet.
Further, the serialization device further comprises a fourth precooling device and a third jacket external bath temperature control device, and the fourth precooling device is arranged at the downstream of the fourth conveying device along the flow direction of the quenching agent; and the third jacket external bath temperature control device is used for controlling the temperature in the fourth precooling device.
Further, the first precooling device, the second precooling device, the third precooling device and the fourth precooling device are respectively and independently selected from a continuous coil pipe reaction device or a continuous stirring kettle reaction device.
The application also provides an application of the continuous low-temperature lithiation aldehyde-adding method in preparing benzaldehyde intermediates, the continuous device is adopted for preparation, and the application comprises the following steps: continuously conveying the raw material liquid and the organic lithium reagent into a continuous lithiation reaction device for continuous lithiation reaction to obtain a lithiation product, and continuously discharging the lithiation product; and continuously conveying the lithiation product and the formylating reagent to perform continuous formylation reaction to obtain a benzaldehyde intermediate, and continuously discharging the benzaldehyde intermediate.
Further, the reaction temperature of the continuous lithiation reaction is-80 to-30 ℃ and the reaction time is 1 to 30min; preferably, the reaction temperature of the continuous lithiation reaction is-60 to-50 ℃ and the reaction time is 5 to 10min.
Further, the reaction temperature of the continuous formylation reaction is-80 to-30 ℃ and the reaction time is 1 to 30min; preferably, the reaction temperature of the continuous formylation reaction is-50 to-40 ℃ and the reaction time is 5 to 10min.
By applying the technical scheme of the application, compared with the traditional batch reactor, the continuous reaction device provided by the application has larger specific surface area; and because of the continuous flow process, the working volume is much smaller than that of the traditional batch reactor, and the mass transfer coefficient and the heat transfer coefficient are higher. This allows for higher (milder) reaction temperatures for continuous flow processes, enabling lower energy consumption. The reaction temperature is increased to make the reaction rate faster and the reaction time shorter, which is beneficial to reducing the risk of side reaction and improving the reaction selectivity. Meanwhile, in the continuous reaction device provided by the application, the reaction raw materials are continuously input, and the reaction products are continuously discharged, so that the production of side reactions is reduced, and the reaction selectivity is improved. In addition, the process has no amplifying effect, which makes the amplifying production of the process easier.
Drawings
The accompanying drawings, which are included to provide a further understanding of the application and are incorporated in and constitute a part of this specification, illustrate embodiments of the application and together with the description serve to explain the application. In the drawings:
fig. 1 shows a schematic structural diagram of a continuous apparatus for preparing a benzaldehyde intermediate by continuous low-temperature lithiation hydroformylation according to a preferred embodiment of the present invention.
Wherein the above figures include the following reference numerals:
10. a continuous lithiation reaction apparatus; 11. a raw material liquid supply device; 12. a second transfer pump; 13. an organolithium reagent supply device; 14. a third transfer pump; 101. a first feed port; 102. a first discharge port; 20. a continuous formylation apparatus; 21. formylating reagent supply means; 22. a first transfer pump; 201. a second feed inlet; 202. a formylating reagent inlet; 203. a second discharge port; 30. a continuous quenching device; 31. a quencher supply means; 32. a fourth conveying device; 301. a third feed inlet; 302. a quencher inlet; 40. a first pre-cooling device; 41. a first jacket external bath temperature control device; 401. a reaction raw material inlet; 402. precooling a raw material liquid outlet; 50. a second pre-cooling device; 501. an organolithium reagent inlet; 502. precooling an organolithium reagent outlet; 60. a third precooling device; 61. a second jacket external bath temperature control device; 70. a fourth precooling device; 71. and a third jacket external bath temperature control device.
Detailed Description
It should be noted that, without conflict, the embodiments of the present application and features of the embodiments may be combined with each other. The present application will be described in detail with reference to examples.
As described in the background art, the existing method for preparing benzaldehyde in batches has the problems of harsh reaction conditions and poor reaction selectivity. In order to solve the above technical problems, the present application provides a continuous device for preparing benzaldehyde intermediates by adopting a continuous low-temperature lithiation hydroformylation process, as shown in fig. 1, the continuous device comprises a continuous lithiation reaction device 10 and a continuous formylation device 20, the continuous lithiation reaction device 10 is provided with a first feed inlet 101 and a first discharge outlet 102, the first feed inlet 101 is used for adding reaction raw materials and organic lithium reagents, and the first discharge outlet 102 is used for continuously discharging a product system of the continuous lithiation reaction; the continuous formylation apparatus 20 is provided with a second feed port 201, a formylation reagent inlet 202 and a second discharge port 203, the second feed port 201 being in communication with the first discharge port 102 so that the product system of the continuous lithiation reaction is continuously fed into the continuous formylation apparatus 20, the formylation reagent inlet 202 being for feeding the formylation reagent, and the second discharge port 203 being for continuously discharging the product system of the continuous formylation reaction.
Compared with the traditional batch reactor, the continuous reaction device provided by the application has larger specific surface area; and because of the continuous flow process, the working volume is much smaller than that of the traditional batch reactor, and the mass transfer coefficient and the heat transfer coefficient are higher. This allows for higher (milder) reaction temperatures for continuous flow processes, enabling lower energy consumption. The reaction temperature is increased to make the reaction rate faster and the reaction time shorter, which is beneficial to reducing the risk of side reaction and improving the reaction selectivity. Meanwhile, in the continuous reaction device provided by the application, the reaction raw materials are continuously input, and the reaction products are continuously discharged, so that the production of side reactions is reduced, and the reaction selectivity is improved. In addition, the process has no amplifying effect, which makes the amplifying production of the process easier.
Some reactive materials will generally remain in the product system of the continuous formylation reaction, which can affect the safety of the process. In order to increase the safety of the process, in a preferred embodiment, as shown in fig. 1, the continuous quenching apparatus further comprises a continuous quenching apparatus 30, the continuous quenching apparatus 30 is provided with a third feed port 301 and a quencher inlet 302, the third feed port 301 is connected with the second discharge port 203 for continuously delivering the product system of the continuous formylation reaction to the continuous quenching apparatus 30, and the quencher inlet 302 is used for adding the quencher. The continuous quenching device 30 is adopted to perform quenching reaction, so that a product system of continuous formylation reaction can be continuously subjected to online quenching, and benzaldehyde intermediates can be continuously discharged, the proportion of byproducts is greatly reduced, the selectivity of the reaction is improved, and meanwhile, the safety of the reaction is also greatly improved due to online quenching.
In a preferred embodiment, continuous lithiation reaction apparatus 10, continuous formylation apparatus 20, and continuous quenching apparatus 30 are each independently selected from a continuous coil reaction apparatus or a continuous stirred tank reaction apparatus.
In the continuous process, whether a continuous coil reactor or a continuous stirred tank reactor is adopted, fresh raw materials continuously flow into the reactor, and a reacted system continuously flows out of an outlet of the reactor. This is favorable to further inhibiting the complex side reaction among the product, intermediate and raw materials generated by the reaction, and improves the reaction selectivity and yield.
In a preferred embodiment, as shown in fig. 1, the continuous device further comprises a first pre-cooling device 40, a second pre-cooling device 50 and a first jacket external bath temperature control device 41, wherein the first pre-cooling device 40 is provided with a reaction raw material inlet 401 and a pre-cooling raw material liquid outlet 402; the second pre-cooling device 50 is provided with an organolithium reagent inlet 501 and a pre-cooling organolithium reagent outlet 502, the pre-cooling raw material liquid outlet 402 and the pre-cooling organolithium reagent outlet 502 are both communicated with the first feed inlet 101, so that the pre-cooling raw material liquid and the pre-cooling organolithium reagent are continuously delivered to the continuous lithiation reaction device 10, and the first jacket external bath temperature control device 41 is used for controlling the temperatures of the first pre-cooling device 40 and the second pre-cooling device 50.
The first precooling device 40, the second precooling device 50 and the first jacket external bath temperature control device 41 can precool the reaction raw material liquid and the lithiation reagent to a specified temperature before the reaction raw material liquid and the lithiation reagent are conveyed to the continuous lithiation reaction device 10, which is favorable for inhibiting the large change of the system temperature caused by mixing the high-temperature raw material liquid and the low-temperature reaction system, and further favorable for inhibiting the occurrence of side reactions.
In a preferred embodiment, as shown in fig. 1, the continuous apparatus further comprises a formylating agent supply means 21 and a first transfer pump 22, the formylating agent supply means 21 being provided with a formylating agent supply port in communication with a formylating agent inlet 202 for continuously transferring formylating agent into the continuous formylating apparatus 20; the first transfer pump 22 is disposed in the flow path between the formylating agent supply port and the formylating agent inlet port 202.
The formylating agent supply device 21 and the first transfer pump 22 are arranged to continuously add formylating agent into the continuous formylating device 20, which is beneficial to improving the continuity of continuous formylating reaction, reducing the labor intensity of operators and improving the selectivity of reaction.
In a preferred embodiment, as shown in fig. 1, the serialization apparatus further comprises a third pre-cooling device 60 and a second jacket external bath temperature control device 61, the third pre-cooling device 60 being disposed downstream of the first delivery pump 22 in the flow direction of the formylating agent; the second jacket external bath temperature control device 61 is used to control the temperature in the third pre-cooling device 60. The third precooling device 60 and the second jacket external bath temperature control device 61 are arranged to precool the formylation reagent before entering the continuous formylation device 20, so that the temperature difference between the formylation reagent and a product system of the continuous lithiation reaction is reduced, the temperature fluctuation is reduced, and the occurrence of side reactions is further suppressed.
In a preferred embodiment, as shown in fig. 1, the continuous apparatus further comprises a raw material liquid supply device 11 and a second transfer pump 12, wherein the raw material liquid supply device 11 is provided with a raw material liquid supply port, and the raw material liquid supply port is communicated with a reaction raw material inlet 401 for continuously transferring the raw material liquid into the first pre-cooling device 40; the second transfer pump 12 is provided in the flow path between the raw material liquid supply port and the reaction raw material inlet 401.
In a preferred embodiment, as shown in fig. 1, the serialization apparatus further includes an organolithium reagent supply apparatus 13 and a third transfer pump 14, the organolithium reagent supply apparatus 13 being provided with an organolithium reagent supply port, the organolithium reagent supply port being in communication with an organolithium reagent inlet 501 for continuously transferring the organolithium reagent into the second precooling apparatus 50; the third transfer pump 14 is provided in the flow path between the organolithium reagent supply port and the organolithium reagent inlet 501.
The arrangement of the raw material liquid supply device 11 and the second delivery pump 12, and the arrangement of the organolithium reagent supply device 13 and the third delivery pump 14 enable the reaction raw material and the organolithium reagent to be continuously added into the continuous formylation device 20, which is beneficial to improving the continuity of continuous lithiation reaction, reducing the labor intensity of operators and improving the selectivity of the reaction.
In a preferred embodiment, as shown in fig. 1, the serialization apparatus further comprises a quencher supply 31 and a fourth delivery means 32, the quencher supply 31 being provided with a quencher supply port in communication with the quencher inlet 302 for continuously delivering the quencher into the continuous quenching apparatus 30; the fourth conveyor 32 is disposed in the flow path between the quencher supply port and the quencher inlet 302.
The arrangement of the quencher supply device 31 and the fourth conveying device 32 can continuously add the quencher to the continuous quenching device 30, which is beneficial to improving the continuity of quenching, reducing the labor intensity of operators and improving the selectivity of the reaction.
In a preferred embodiment, as shown in fig. 1, the serialization apparatus further comprises a fourth pre-cooling apparatus 70 and a third jacket external bath temperature control apparatus 71, the fourth pre-cooling apparatus 70 being disposed downstream of the fourth conveying apparatus 32 in the flow direction of the quencher, the third jacket external bath temperature control apparatus 71 being used to control the temperature in the fourth pre-cooling apparatus 70. The fourth precooling device 70 and the third jacket external bath temperature control device 71 are arranged to precool the quenching agent before entering the continuous quenching device 30, so that the temperature difference between the quenching agent and a product system of the continuous formylation reaction is reduced, the temperature fluctuation is reduced, and the occurrence of side reactions is further suppressed.
The use of a continuous precooling apparatus enables the material to be precooled to be continuously precooled, which is advantageous in improving the selectivity and yield of the reaction, and more preferably, the first precooling apparatus 40, the second precooling apparatus 50, the third precooling apparatus 60 and the fourth precooling apparatus 70 are each independently selected from a continuous coil reactor or a continuous stirred tank reactor.
The application also provides an application of the continuous low-temperature lithiation aldehyde-adding method in preparing benzaldehyde intermediates, the continuous device is adopted for preparation, and the application comprises the following steps: continuously conveying the raw material liquid and the organic lithium reagent into a continuous lithiation reaction device 10 for continuous lithiation reaction to obtain a lithiation product, and continuously discharging the lithiation product; and continuously conveying the lithiation product and the formylating reagent to perform continuous formylation reaction to obtain a benzaldehyde intermediate, and continuously discharging the benzaldehyde intermediate.
Compared with the traditional batch reactor, the continuous reaction device provided by the application has larger specific surface area; and because of the continuous flow process, the working volume is much smaller than that of the traditional batch reactor, and the mass transfer coefficient and the heat transfer coefficient are higher. This allows for higher (milder) reaction temperatures for continuous flow processes, enabling lower energy consumption. The reaction temperature is increased to make the reaction rate faster and the reaction time shorter, which is beneficial to reducing the risk of side reaction and improving the reaction selectivity. Meanwhile, in the continuous reaction device provided by the application, the reaction raw materials are continuously input, and the reaction products are continuously discharged, so that the production of side reactions is reduced, and the reaction selectivity is improved. In addition, the process has no amplifying effect, which makes the amplifying production of the process easier. On the basis, the continuous device is favorable for improving the reaction temperature, the reaction selectivity and the product yield when the benzaldehyde intermediate is prepared.
In order to reduce the influence of external factors on the product yield, it is preferable to replace the gas in the continuous reaction apparatus with an inert gas or nitrogen gas before the continuous reaction is performed. The inert gas is supplied from an inert gas supply device.
In a preferred embodiment, the reaction temperature of the continuous lithiation reaction is-80 to-30 ℃ and the reaction time is 1 to 30min. The reaction temperature and the reaction time of the continuous lithiation reaction include, but are not limited to, the above ranges, and limiting them to the above ranges is advantageous in further improving the yield of the continuous lithiation reaction. More preferably, the reaction temperature of the continuous lithiation reaction is-60 to-50 ℃ and the reaction time is 5 to 10min.
In a preferred embodiment, the reaction temperature of the continuous formylation reaction is from-80 to-30℃and the reaction time is from 1 to 30min. The reaction temperature and the reaction time of the continuous formylation reaction include, but are not limited to, the above-mentioned ranges, and limiting them to the above-mentioned ranges is advantageous in further improving the yield of the continuous lithiation reaction. More preferably, the reaction temperature of the continuous formylation reaction is-50 to-40 ℃ and the reaction time is 5 to 10min.
In a preferred embodiment, the above application further comprises: the product system of the continuous formylation reaction is continuously conveyed to the continuous quenching device 30 for continuous quenching reaction, the obtained benzaldehyde intermediate is quenched by the continuous quenching device 30, the product system of the continuous formylation reaction can be continuously quenched on line, and the benzaldehyde intermediate can be continuously discharged, so that the proportion of byproducts is greatly reduced, the selectivity of the reaction is improved, and meanwhile, the safety of the reaction is greatly improved due to the on-line quenching.
The application is described in further detail below in connection with specific examples which are not to be construed as limiting the scope of the application as claimed.
Example 1
The device shown in figure 1 is adopted to prepare the benzaldehyde intermediate, and the specific operation flow is as follows:
The prepared solution of 2-bromo-4-fluorobenzaldehyde in tert-butyl tetrahydrofuran (1.0 equivalent) was output from the raw material liquid supply device 11, conveyed to the continuous coil reactor of the first precooling device 40 by the second conveying pump 12, and lithium diisopropylamide (1.1 equivalent) was conveyed to the second precooling device 50 by the third conveying pump 14 by the organolithium reagent supply device 13, and subjected to temperature control under the action of the first jacket external bath temperature control device 41. The precooled raw material solution and the organic lithium reagent solution are mixed in the continuous lithiation reaction device 10 and undergo continuous lithiation reaction in the first stage to obtain a lithiation product. In the reaction process, the raw material solution and the organic lithium reagent solution are continuously input into the continuous lithiation reaction apparatus 10 through the first feed port 101, and the product system after the continuous lithiation reaction is continuously discharged from the first discharge port 102 and is continuously conveyed into the continuous formylating apparatus 20 through the second feed port 201.
The formylating agent (2.0 equivalents) supplied from the formylating agent supply means 21 is fed to the third precooling means 60 by the first transfer pump 22, precooled by the second jacket external bath temperature control means 61, and then continuously fed to the continuous formylating means 20 through the second feed port 201 to perform continuous formylation reaction with the product system of the continuous lithiation reaction. The reacted product system is continuously discharged through the second discharge port 203 and continuously conveyed into the continuous quenching reaction device through the third feed port 301. The quencher (acetic acid, 3.0 equivalents) supplied from the quencher supply means 31 is continuously fed to the fourth precooling means 70 via the fourth feeding means 32, and precooling is performed by the third jacket external bath temperature control means 71. The pre-cooled quencher is then continuously fed to the continuous quenching apparatus 30 for continuous quenching reactions. And continuously discharging the quenched system, and performing subsequent treatment to obtain the required benzaldehyde intermediate. The parameters in the reaction are shown in Table 1.
The synthetic route is as follows:
Example 2
The differences from example 1 are: the reaction temperature of the continuous lithiation reaction was-20 ℃ and the reaction time was 40min.
Example 3
The differences from example 1 are: the reaction temperature of the continuous formylation reaction was-20℃and the reaction time was 40min.
Comparative example 1
The differences from example 1 are: the benzaldehyde intermediate is prepared by adopting a batch process, and the reaction device is an intermittent reaction kettle.
TABLE 1
From the above description, it can be seen that the above embodiments of the present application achieve the following technical effects: compared with the traditional batch reaction, the continuous synthesis method provided by the application is beneficial to greatly improving the yield of the benzaldehyde intermediate.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (9)
1. The application of a continuous low-temperature lithiation aldehyde group-adding method in the preparation of benzaldehyde intermediates is characterized in that the preparation is carried out by adopting a continuous device, and the continuous device comprises:
The continuous lithiation reaction device (10), wherein the continuous lithiation reaction device (10) is provided with a first feed inlet (101) and a first discharge outlet (102), the first feed inlet (101) is used for adding reaction raw materials and organic lithium reagents, and the first discharge outlet (102) is used for continuously discharging a product system of the continuous lithiation reaction; the reaction raw material is 2-bromo-4-fluorobenzaldehyde tert-butyl tetrahydrofuran solution, and the organolithium reagent is lithium diisopropylamide;
A continuous formylation apparatus (20), the continuous formylation apparatus (20) being provided with a second feed inlet (201), a formylation reagent inlet (202) and a second discharge outlet (203), the second feed inlet (201) being in communication with the first discharge outlet (102) so that the product system of the continuous lithiation reaction is continuously fed into the continuous formylation apparatus (20), the formylation reagent inlet (202) being for feeding a formylation reagent, and the second discharge outlet (203) being for continuously discharging the product system of the continuous formylation reaction; the formylating reagent is DMF;
the application comprises:
Continuously conveying the raw material liquid and the organic lithium reagent into a continuous lithiation reaction device (10) for continuous lithiation reaction to obtain a lithiation product, and continuously discharging the lithiation product; the reaction temperature of the continuous lithiation reaction is-60 to-50 ℃ and the reaction time is 5-10 min;
Continuously conveying the lithiation product and a formylation reagent to a continuous formylation device (20) for continuous formylation reaction to obtain the benzaldehyde intermediate, and continuously discharging the benzaldehyde intermediate; the reaction temperature of the continuous formylation reaction is-50 to-40 ℃ and the reaction time is 5 to 10min;
Continuously conveying the product system of the continuous formylation reaction to a continuous quenching device (30) for continuous quenching reaction to obtain the benzaldehyde intermediate; the serialization device further comprises a continuous quenching device (30), the continuous quenching device (30) is provided with a third feed inlet (301) and a quenching agent inlet (302), the third feed inlet (301) is communicated with the second discharge outlet (203) and is used for continuously conveying a product system of the continuous formylation reaction to the continuous quenching device (30), the quenching agent inlet (302) is used for adding a quenching agent, and the continuous lithiation reaction device (10), the continuous formylation device (20) and the continuous quenching device (30) are respectively and independently selected from a continuous coil reaction device or a continuous stirred tank reaction device.
2. The use of claim 1, wherein the serialization apparatus further comprises:
A first pre-cooling device (40), wherein the first pre-cooling device (40) is provided with a reaction raw material inlet (401) and a pre-cooling raw material liquid outlet (402);
A second pre-cooling device (50), wherein the second pre-cooling device (50) is provided with an organolithium reagent inlet (501) and a pre-cooling organolithium reagent outlet (502);
a first jacket external bath temperature control device (41), wherein the first jacket external bath temperature control device (41) is used for controlling the temperatures of the first pre-cooling device (40) and the second pre-cooling device (50);
The precooling raw material liquid outlet (402) and the precooling organic lithium reagent outlet (502) are communicated with the first feed inlet (101) so that the precooling raw material liquid and the precooling organic lithium reagent are continuously conveyed to the continuous lithiation reaction device (10).
3. The use of claim 2, wherein the serialization apparatus further comprises:
A formylating agent supply device (21), the formylating agent supply device (21) being provided with a formylating agent supply port, which formylating agent supply port communicates with the formylating agent inlet (202) for continuously conveying the formylating agent into the continuous formylating device (20);
a first transfer pump (22), the first transfer pump (22) being disposed on a flow path between the formylating agent supply port and the formylating agent inlet port (202).
4. The use according to claim 3, wherein the serialization apparatus further comprises:
A third pre-cooling device (60), the third pre-cooling device (60) being arranged downstream of the first delivery pump (22) in the flow direction of the formylating agent; and
And a second jacket external bath temperature control device (61), wherein the second jacket external bath temperature control device (61) is used for controlling the temperature in the third precooling device (60).
5. The use of claim 4, wherein the serialization apparatus further comprises:
a raw material liquid supply device (11), wherein the raw material liquid supply device (11) is provided with a raw material liquid supply port, and the raw material liquid supply port is communicated with the reaction raw material inlet (401) and is used for continuously conveying raw material liquid into the first precooling device (40);
And a second transfer pump (12), wherein the second transfer pump (12) is provided in a flow path between the raw material liquid supply port and the reaction raw material inlet (401).
6. The use of claim 5, wherein the serialization apparatus further comprises:
an organolithium reagent supply device (13), wherein the organolithium reagent supply device (13) is provided with an organolithium reagent supply port, the organolithium reagent supply port is communicated with the organolithium reagent inlet (501), and the organolithium reagent supply device (13) is used for continuously conveying the organolithium reagent into the second precooling device (50);
And a third transfer pump (14), wherein the third transfer pump (14) is arranged on a flow path between the organolithium reagent supply port and the organolithium reagent inlet (501).
7. The use of claim 6, wherein the serialization apparatus further comprises:
A quencher supply means (31), said quencher supply means (31) being provided with a quencher supply port in communication with said quencher inlet (302) for continuously delivering quencher into said continuous quenching means (30);
-fourth conveying means (32), said fourth conveying means (32) being arranged in a flow path between said quencher supply mouth and said quencher inlet (302).
8. The use of claim 7, wherein the serialization apparatus further comprises:
A fourth pre-cooling device (70), the fourth pre-cooling device (70) being arranged downstream of the fourth conveying device (32) in the flow direction of the quenching agent; and
And a third jacket external bath temperature control device (71), wherein the third jacket external bath temperature control device (71) is used for controlling the temperature in the fourth precooling device (70).
9. The use according to claim 8, wherein the first pre-cooling device (40), the second pre-cooling device (50), the third pre-cooling device (60) and the fourth pre-cooling device (70) are each independently selected from a continuous coil reactor or a continuous stirred tank reactor.
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| CN110386864A (en) * | 2019-08-15 | 2019-10-29 | 天津凯莱英制药有限公司 | The method for continuously synthesizing of 2,4,6- trifluro benzaldehydes |
| CN110559958B (en) * | 2019-09-12 | 2021-09-07 | 凯莱英医药化学（阜新）技术有限公司 | Device for continuously preparing 2, 6-dihydroxy benzaldehyde and application thereof |
| JP7312317B2 (en) * | 2019-09-12 | 2023-07-20 | アシムケム ラボラトリーズ （フーシン） カンパニー リミテッド | Continuous production apparatus for 2,6-dihydroxybenzaldehyde and its use |
| CN110835292A (en) * | 2019-10-12 | 2020-02-25 | 北京海美桐医药科技有限公司 | Method for preparing 2-fluoro-6-trifluoromethylbenzaldehyde by adopting continuous flow reaction device |
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