CN108892616A - Prepare continuous device and its application of benzaldehydes intermediate - Google Patents

Abstract

The invention provides a continuous device for preparing benzaldehyde intermediates and its application. The continuous device includes a continuous lithiation reaction device and a continuous formylation device. The continuous lithiation reaction device is provided with a first feed port and a first discharge port, the first feed port is used to add reaction raw materials and organolithium reagents, and the first discharge port is used to continuously feed the product system of the continuous lithiation reaction. Discharge; the continuous formylation device is provided with a second feed port, a formylating reagent inlet and a second discharge port, and the second feed port is connected with the first discharge port so that the product system of the continuous lithiation reaction It is continuously transported to the continuous formylation device, the inlet of the formylation reagent is used for adding the formylation reagent, and the second outlet is used for continuously discharging the product system of the continuous formylation reaction. The adoption of the device is beneficial to improve reaction selectivity, reduce energy consumption, and is also convenient for industrialized production.

Description

Continuous device for preparing benzaldehyde intermediates and its application

technical field

The invention relates to the field of synthesis of pharmaceutical intermediates, in particular to a continuous device for preparing benzaldehyde intermediates and its application.

Background technique

Benzaldehyde intermediates are a common and very important pharmaceutical intermediates. There are many synthesis methods, mainly including toluene oxidation, Vilsmeier reaction formylation of aromatic rings, direct insertion of carbonyls on benzene rings, low-temperature lithiation of aldehyde groups, and so on. Among them, low-temperature lithiation of aldehyde groups is a very classic synthesis method, which can form a very good complementarity with other synthesis methods.

Using the traditional batch reaction process, the process of the low-temperature lithiation aldehyde group method is as follows: the raw materials and solvents are added to the reactor, and stirred and dissolved under the protection of nitrogen. Then, under the protection of an inert gas, the temperature of the raw material solution was lowered to -78°C. At the same time, the temperature was controlled at -78°C, and lithium diisopropylamide solution was added dropwise to the reaction system. After the dropwise addition, the reaction system was kept stirring for 0.5-1.5 hours. The temperature of the reaction system was continuously controlled to -78°C, and N,N-dimethylformamide was added dropwise into the reaction system. After the dropwise addition, the system was kept warm and stirred for 10 min. Then the acid solution was added dropwise to quench the system.

When using the traditional batch reaction process for low-temperature lithiation, there are usually the following disadvantages:

1. Requires very low reaction temperature, high energy consumption and high cost. In the low-temperature lithiation process of batch reaction disclosed in the existing literature, the reaction temperature usually needs to be controlled below -70°C.

2. The batch reaction is a fully mixed flow reaction method, which will make the highly active lithium salt intermediates generated in the reaction process evenly or nearly uniformly dispersed in the reaction system, which is very unfavorable for substrates containing active groups in the structure , the highly active lithium salt intermediate will react with the active group in the structure, thereby making the selectivity of the reaction worse, resulting in a low yield of the main reaction and a low purity of the system.

3. The amplification effect is obvious, and the process is not easy to enlarge. Aldehyde group reaction on low temperature lithiation, usually the heat of reaction is very large. Scale-up using batch reactors with inefficient mass and heat transfer can lead to severe scale-up effects. Thereby the purity and yield are greatly reduced. And after the process is enlarged, in order to control the temperature of the system, the dropping rate of the material 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.

Contents of the invention

The main purpose of the present invention is to provide a continuous device for preparing benzaldehyde intermediates and its application, so as to solve the problems of harsh reaction conditions and poor reaction selectivity in the existing method for preparing benzaldehyde in batches.

In order to achieve the above object, according to one aspect of the present invention, a continuous device for preparing benzaldehyde intermediates is provided. The continuous device includes a continuous lithiation reaction device and a continuous formylation device. The continuous lithiation reaction device is provided with a first feed port and a first discharge port, the first feed port is used to add reaction raw materials and organolithium reagents, and the first discharge port is used to continuously feed the product system of the continuous lithiation reaction. Discharge; the continuous formylation device is provided with a second feed port, a formylating reagent inlet and a second discharge port, and the second feed port is connected with the first discharge port so that the product system of the continuous lithiation reaction It is continuously transported to the continuous formylation device, the inlet of the formylation reagent is used for adding the formylation reagent, and the second outlet is used for continuously discharging the product system of the continuous formylation reaction.

Further, the continuous device also includes a continuous quenching device, the continuous quenching device is provided with a third feed port and a quenching agent inlet, the third feed port communicates with the second discharge port and is used to continuously formylate The product system of the reaction is continuously sent to the continuous quenching device, and the quenching agent inlet is used for adding the quenching agent.

Further, the continuous lithiation reaction device, the continuous formylation device and the continuous quenching device are independently selected from a continuous coil reaction device or a continuous stirred tank reaction device.

Further, the continuous device also includes a first pre-cooling device, a second pre-cooling device and a first jacket outer bath temperature control device, the first pre-cooling device is provided with a reaction raw material inlet and a pre-cooled raw material liquid outlet; the second pre-cooling device The cooling device is provided with an organolithium reagent inlet and a precooling organolithium reagent outlet; the first jacket outer bath temperature control device is used to control the temperature of the first precooling device and the second precooling device; the precooling raw material liquid outlet and the precooling The organolithium reagent outlets are all connected to the first feed inlet, so that the pre-cooled raw material liquid and the pre-cooled organolithium reagent are continuously delivered to the continuous lithiation reaction device.

Further, the continuous device also includes a formylating reagent supply device and a first delivery pump. The formylation reagent supply device is provided with a formylation reagent supply port, and the formylation reagent supply port is connected with the formylation reagent inlet, and is used to continuously transport the formylation reagent to the continuous formylation device; the first transport The pump is provided on the flow path between the formylating reagent supply port and the formylating reagent inlet.

Further, the continuous device also includes a third precooling device and a second jacket outer bath temperature control device. Along the flow direction of the formylation reagent, the third precooling device is arranged downstream of the first delivery pump; and the second jacket outer bath temperature control device is used to control the temperature in the third precooling device.

Further, the continuous device also includes a raw material liquid supply device and a second delivery pump, the raw material liquid supply device is provided with a raw material liquid supply port, and the raw material liquid supply port is connected with the reaction raw material inlet for continuously feeding the first precooling device The raw material liquid is conveyed in the center; the second delivery pump is arranged on the flow path between the raw material liquid supply port and the reaction raw material inlet.

Further, the continuous device also includes an organolithium reagent supply device and a third delivery pump, the organolithium reagent supply device is provided with an organolithium reagent supply port, the organolithium reagent supply port is connected with the organolithium reagent inlet, and the organolithium reagent supply device It is used to continuously deliver the organic lithium reagent to the second pre-cooling device; the third delivery pump is arranged on the flow path between the organic lithium reagent supply port and the organic lithium reagent inlet.

Further, the continuous device also includes a quenching agent supply device and a fourth delivery device, the quenching agent supply device is provided with a quenching agent supply port, and the quenching agent supply port communicates with the quenching agent inlet for continuously feeding The quenching agent is conveyed in the continuous quenching device; the fourth conveying device is arranged on the flow path between the quenching agent supply port and the quenching agent inlet.

Further, the continuous device also includes a fourth pre-cooling device and a third jacket outer bath temperature control device, along the flow direction of the quenching agent, the fourth pre-cooling device is arranged downstream of the fourth delivery device; and the third clamp The outer bath temperature control device is used to control 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 independently selected from a continuous coil reaction device or a continuous stirred tank reaction device.

Another aspect of the present application also provides an application of the continuous low-temperature lithiation aldehyde method in the preparation of benzaldehyde intermediates, which is prepared by using the above-mentioned continuous device. The lithiation product is continuously transported to the continuous lithiation reaction device for continuous lithiation reaction to obtain the lithiation product, and the lithiation product is continuously discharged; the lithiation product and the formylation reagent are continuously transported to the continuous formylation reaction to obtain benzene formaldehyde intermediates, and continuously discharge benzaldehyde intermediates.

Further, the reaction temperature of the continuous lithiation reaction is -80 to -30°C, and the reaction time is 1 to 30 minutes; preferably, the reaction temperature of the continuous lithiation reaction is -60 to -50°C, and the reaction time is 5 to 10 minutes.

Further, the reaction temperature of the continuous formylation reaction is -80 to -30°C, and the reaction time is 1 to 30 minutes; preferably, the reaction temperature of the continuous formylation reaction is -50 to -40°C, and the reaction time is 5 to 30 minutes. 10min.

Applying the technical scheme of the present invention, compared with traditional batch reactors, the specific surface area of the continuous reaction device provided by the application is larger; and because it is a continuous flow process, its working volume is much smaller than that of traditional batch reactors, and at the same time Higher mass and heat transfer coefficients. This allows for higher (gentle) reaction temperatures in the continuous flow process, which can reduce energy consumption. The increase of the reaction temperature makes the reaction rate faster and the reaction time shorter, which is beneficial to reduce the risk of side reactions and improve the reaction selectivity. At the same time, in the continuous reaction device provided by the present application, the reaction raw materials are continuously input and the reaction products are continuously discharged, which is also beneficial to reduce the generation of side reactions and improve the selectivity of the reaction. In addition, the process basically has no amplification effect, which makes the scale-up production of the process easier.

Description of drawings

The accompanying drawings constituting a part of the present application are used to provide a further understanding of the present invention, and the schematic embodiments and descriptions of the present invention are used to explain the present invention, and do not constitute an improper limitation of the present invention. In the attached picture:

Fig. 1 shows a schematic structural diagram of a continuous device for preparing benzaldehyde intermediates by continuous low-temperature lithiation on aldehydes according to a preferred embodiment of the present invention.

Wherein, the above-mentioned accompanying drawings include the following reference signs:

10. Continuous lithiation reaction device; 11. Raw material liquid supply device; 12. Second delivery pump; 13. Organic lithium reagent supply device; 14. Third delivery pump; 101. First feed inlet; 102. First outlet Material inlet; 20, continuous formylation device; 21, formylation reagent supply device; 22, first delivery pump; 201, second feed inlet; 202, formylation reagent inlet; 203, second outlet 30. Continuous quenching device; 31. Quenching agent supply device; 32. The fourth conveying device; 301. The third feeding port; 302. Quenching agent inlet; 40. The first pre-cooling device; 41. The first Jacket outer bath temperature control device; 401, reaction raw material inlet; 402, pre-cooling raw material liquid outlet; 50, second pre-cooling device; 501, organolithium reagent inlet; 502, pre-cooling organolithium reagent outlet; 60, third Pre-cooling device; 61. The second jacket outer bath temperature control device; 70. The fourth pre-cooling device; 71. The third jacket outer bath temperature control device.

Detailed ways

It should be noted that, in the case of no conflict, the embodiments in the present application and the features in the embodiments can be combined with each other. The present invention will be described in detail below in conjunction with examples.

As described in the background technology, the existing methods for preparing benzaldehyde in batches have the problems of harsh reaction conditions and poor reaction selectivity. In order to solve the above-mentioned technical problems, the application provides a continuous low-temperature lithiation aldehyde method to prepare a continuous device for benzaldehyde intermediates, as shown in Figure 1, the continuous device includes a continuous lithiation reaction device 10 and Continuous formylation device 20, continuous lithiation reaction device 10 is provided with a first feed port 101 and a first discharge port 102, the first feed port 101 is used to add reaction raw materials and organolithium reagents, the first discharge port 102 is used to continuously discharge the product system of the continuous lithiation reaction; the continuous formylation device 20 is provided with a second feed port 201, a formylation reagent inlet 202 and a second discharge port 203, and the second feed port 201 is connected to the second feed port 203. The first discharge port 102 is connected, so that the product system of the continuous lithiation reaction is continuously delivered to the continuous formylation device 20, the formylation reagent inlet 202 is used to add the formylation reagent, and the second discharge port 203 It is used to continuously discharge the product system of the continuous formylation reaction.

Compared with traditional batch reactors, the continuous reaction device provided by this application has a larger specific surface area; and because it is a continuous flow process, its working volume is much smaller than that of traditional batch reactors, and the mass transfer coefficient and heat transfer coefficient higher. This allows for higher (gentle) reaction temperatures in the continuous flow process, which can reduce energy consumption. The increase of the reaction temperature makes the reaction rate faster and the reaction time shorter, which is beneficial to reduce the risk of side reactions and improve the reaction selectivity. At the same time, in the continuous reaction device provided by the present application, the reaction raw materials are continuously input and the reaction products are continuously discharged, which is also beneficial to reduce the generation of side reactions and improve the selectivity of the reaction. In addition, the process basically has no amplification effect, which makes the scale-up production of the process easier.

In the product system of continuous formylation reaction, some reactive materials usually remain, which will affect the safety of the process. In order to improve the safety of the process, in a preferred embodiment, as shown in Figure 1, the continuous device also includes a continuous quenching device 30, the continuous quenching device 30 is provided with a third feed port 301 and quenching The agent inlet 302, the third feed port 301 is connected with the second outlet 203 for continuously conveying the product system of the continuous formylation reaction to the continuous quenching device 30, and the quenching agent inlet 302 is used for adding the quenching agent . Adopting continuous quenching device 30 to carry out quenching reaction, the product system of continuous formylation reaction can be continuously quenched online, and the benzaldehyde intermediates can be discharged continuously, which greatly reduces the production of by-products The ratio improves the selectivity of the reaction, and the online quenching also greatly improves the safety of the reaction.

In a preferred embodiment, the continuous lithiation reaction device 10 , the continuous formylation device 20 and the continuous quenching device 30 are independently selected from a continuous coil reaction device or a continuous stirred tank reaction device.

In the above continuous process, whether it is a continuous coil reactor or a continuous stirred tank reactor, fresh raw materials are continuously flowing into the reactor, and at the same time, the reacted system is continuously flowing out from the outlet of the reactor. This is conducive to further suppressing the complex side reactions between the products, intermediates and raw materials generated by the reaction, and improving the reaction selectivity and yield.

In a preferred embodiment, as shown in Figure 1, the continuous device also includes a first pre-cooling device 40, a second pre-cooling device 50 and a first jacket outer bath temperature control device 41, the first pre-cooling device The device 40 is provided with a reaction raw material inlet 401 and a precooling raw material liquid outlet 402; the second precooling device 50 is provided with an organolithium reagent inlet 501 and a precooling organolithium reagent outlet 502, and a precooling raw material liquid outlet 402 and a precooling organolithium reagent The outlets 502 are all connected with the first feed inlet 101, so that the precooled raw material liquid and the precooled organolithium reagent are continuously delivered to the continuous lithiation reaction device 10, and the first jacket outer bath temperature control device 41 is used to control the second The temperature of the first pre-cooling device 40 and the second pre-cooling device 50 .

The first pre-cooling device 40, the second pre-cooling device 50 and the first jacket outer bath temperature control device 41 can be pre-cooled before the reaction raw material liquid and the lithiation reagent are delivered to the continuous lithiation reaction device 10. To the specified temperature, which is beneficial to suppress the large change in system temperature caused by the mixing of high-temperature feed liquid and low-temperature reaction system, and further helps to suppress the occurrence of side reactions.

In a preferred embodiment, as shown in Figure 1, the continuous device also includes a formylating reagent supply device 21 and a first delivery pump 22, and the formylating reagent supply device 21 is provided with a formylating reagent supply port , the formylation reagent supply port is in communication with the formylation reagent inlet 202, and is used to continuously transport the formylation reagent to the continuous formylation device 20; the first delivery pump 22 is arranged between the formylation reagent supply port and the On the flow path between the acylating reagent inlets 202.

The arrangement of the formylation reagent supply device 21 and the first delivery pump 22 can make it continuously add the formylation reagent to the continuous formylation device 20, which is conducive to improving the continuity of the continuous formylation reaction and reducing the number of operators. The labor intensity is improved, and the selectivity of the reaction is improved.

In a preferred embodiment, as shown in Figure 1, the continuous device also includes a third precooling device 60 and a second jacket outer bath temperature control device 61, along the flow direction of the formylating reagent, the third The pre-cooling device 60 is arranged downstream of the first delivery pump 22 ; the second jacket outer bath temperature control device 61 is used to control the temperature in the third pre-cooling device 60 . Setting the third precooling device 60 and the second jacket outer bath temperature control device 61 can make the formylation reagent precool before entering the continuous formylation device 20, which is beneficial to reduce the impact of the formylation reagent on continuous lithiation. The temperature difference between the product systems of the reaction reduces temperature fluctuations, which is beneficial to further inhibit the occurrence of side reactions.

In a preferred embodiment, as shown in Figure 1, the continuous device also includes a raw material liquid supply device 11 and a second delivery pump 12, the raw material liquid supply device 11 is provided with a raw material liquid supply port, and the raw material liquid supply port is connected to the The reaction raw material inlet 401 is connected to continuously deliver the raw material liquid to the first pre-cooling device 40 ; the second delivery pump 12 is arranged on the flow path between the raw material liquid supply port and the reaction raw material inlet 401 .

In a preferred embodiment, as shown in Figure 1, the continuous device also includes an organolithium reagent supply device 13 and a third delivery pump 14, the organolithium reagent supply device 13 is provided with an organolithium reagent supply port, and the organolithium reagent supply device 13 is provided with an organolithium reagent supply port. The reagent supply port communicates with the organolithium reagent inlet 501 for continuously delivering the organolithium reagent to the second precooling device 50; the third transport pump 14 is arranged between the organolithium reagent supply port and the organolithium reagent inlet 501 on the stream.

The setting of the raw material liquid supply device 11 and the second transfer pump 12, and the arrangement of the organolithium reagent supply device 13 and the third transfer pump 14 can make it continuously add the reaction raw materials and the organolithium reagent in the continuous formylation device 20, This is conducive to improving the continuity of the continuous lithiation reaction, reducing the labor intensity of the operator, and improving the selectivity of the reaction.

In a preferred embodiment, as shown in FIG. 1, the continuous device further includes a quenching agent supply device 31 and a fourth delivery device 32, the quenching agent supply device 31 is provided with a quenching agent supply port, and the quenching agent The agent supply port is in communication with the quenching agent inlet 302, and is used to continuously deliver the quenching agent to the continuous quenching device 30; on the way.

The setting of the quenching agent supply device 31 and the fourth conveying device 32 can make it continuously add the quenching agent to the continuous quenching device 30, which is beneficial to improve the continuity of quenching, reduce the labor intensity of the operator, and improve the reaction rate. selectivity.

In a preferred embodiment, as shown in Figure 1, the continuous device also includes a fourth pre-cooling device 70 and a third jacket outer bath temperature control device 71, along the flow direction of the quenching agent, the fourth pre-cooling device The cooling device 70 is arranged downstream of the fourth conveying device 32 , and the third jacket outer bath temperature control device 71 is used to control the temperature in the fourth pre-cooling device 70 . Setting the fourth pre-cooling device 70 and the third jacket outer bath temperature control device 71 can make the quenching agent pre-cooled before entering the continuous quenching device 30, thereby helping to reduce the interaction between the quenching agent and the continuous formylation reaction. The temperature difference between the product systems reduces temperature fluctuations, which is beneficial to further inhibit the occurrence of side reactions.

Adopting the continuous precooling device can make the material to be precooled continuously precooled, which is conducive to improving the selectivity and yield of the reaction. More preferably, the first precooling device 40, the second precooling device 50, The third precooling device 60 and the fourth precooling device 70 are respectively independently selected from a continuous coil reaction device or a continuous stirred tank reaction device.

Another aspect of the present application also provides an application of the continuous low-temperature lithiation aldehyde method in the preparation of benzaldehyde intermediates, which is prepared by using the above-mentioned continuous device. The lithiation product is continuously transported to the continuous lithiation reaction device 10 for continuous lithiation reaction to obtain the lithiation product, and the lithiation product is continuously discharged; the lithiation product and the formylation reagent are continuously transported to the continuous formylation reaction to obtain Benzaldehyde intermediates, and the benzaldehyde intermediates are discharged continuously.

Compared with traditional batch reactors, the continuous reaction device provided by this application has a larger specific surface area; and because it is a continuous flow process, its working volume is much smaller than that of traditional batch reactors, and the mass transfer coefficient and heat transfer coefficient higher. This allows for higher (gentle) reaction temperatures in the continuous flow process, which can reduce energy consumption. The increase of the reaction temperature makes the reaction rate faster and the reaction time shorter, which is beneficial to reduce the risk of side reactions and improve the reaction selectivity. At the same time, in the continuous reaction device provided by the present application, the reaction raw materials are continuously input and the reaction products are continuously discharged, which is also beneficial to reduce the generation of side reactions and improve the selectivity of the reaction. In addition, the process basically has no amplification effect, which makes the scale-up production of the process easier. On this basis, when the above-mentioned continuous device is used to prepare the benzaldehyde intermediates, it is beneficial to improve the temperature of the reaction, the selectivity of the reaction and the yield of the product.

In order to reduce the impact of external factors on the product yield, preferably, before performing the continuous reaction, use inert gas or nitrogen to replace the gas in the continuous reaction device. The inert gas is provided by an inert gas supply.

In a preferred embodiment, the reaction temperature of the continuous lithiation reaction is -80 to -30° C., and the reaction time is 1 to 30 minutes. The reaction temperature and reaction time of the continuous lithiation reaction include but are not limited to the above range, and limiting them within the above range is beneficial to further improve the yield of the continuous lithiation reaction. More preferably, the reaction temperature of the continuous lithiation reaction is -60 to -50° C., and the reaction time is 5 to 10 minutes.

In a preferred embodiment, the reaction temperature of the continuous formylation reaction is -80 to -30°C, and the reaction time is 1 to 30 minutes. The reaction temperature and reaction time of the continuous formylation reaction include but are not limited to the above-mentioned range, and limiting them within the above-mentioned range is beneficial to further improve the yield of the continuous lithiation reaction. More preferably, the reaction temperature of the continuous formylation reaction is -50 to -40°C, and the reaction time is 5 to 10 minutes.

In a preferred embodiment, the above-mentioned application also includes: continuously transporting the product system of the continuous formylation reaction to the continuous quenching device 30 for continuous quenching reaction, and adopting the continuous quenching device to obtain the benzaldehyde intermediate 30 for quenching reaction, can continuously quench the product system of continuous formylation reaction online, and can also continuously discharge benzaldehyde intermediates, which greatly reduces the proportion of by-products and improves the reaction rate. At the same time, the online quenching also greatly improves the safety of the reaction.

The present application will be described in further detail below in conjunction with specific examples, and these examples should not be construed as limiting the scope of protection claimed in the present application.

Example 1

Adopt the device as shown in Figure 1 to prepare benzaldehyde intermediate, concrete operating process is as follows:

The prepared 2-bromo-4-fluorobenzaldehyde tert-butyl tetrahydrofuran solution (1.0 equivalent) is output from the raw material liquid supply device 11, and is transported to the first precooling device 40 continuous coil reactor through the second delivery pump 12 , Lithium diisopropylamide (1.1 equivalents) is transported to the second pre-cooling unit 50 by the organolithium reagent supply unit 13 by the third delivery pump 14, and is carried out under the effect of the first jacket outer bath temperature control unit 41 temperature control. The pre-cooled raw material solution and the organic lithium reagent solution are mixed in the continuous lithiation reaction device 10 and undergo a first-stage continuous lithiation reaction to obtain a lithiation product. During the reaction, the raw material solution and the organic lithium reagent solution are continuously input into the continuous lithiation reaction device 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 It is continuously transported to the continuous formylation device 20 through the second feed port 201 .

The formylation reagent (2.0 equivalents) supplied by the formylation reagent supply device 21 is transported in the third precooling device 60 through the first delivery pump 22, and is pre-cooled under the effect of the second jacket outer bath temperature control device 61. Then, it is continuously transported to the continuous formylation device 20 through the second feed port 201, and the continuous formylation reaction is carried out with the product system of the continuous lithiation reaction. The reacted product system is continuously discharged through the second discharge port 203 and continuously transported to the continuous quenching reaction device through the third feed port 301 . The quenching agent (acetic acid, 3.0 equivalents) provided by the quenching agent supply device 31 is continuously delivered to the fourth pre-cooling device 70 through the fourth delivery device 32, and under the action of the third jacket outer bath temperature control device 71 Pre-cool. Then the pre-cooled quenching agent is continuously delivered to the continuous quenching device 30 for continuous quenching reaction. The quenched system is continuously discharged, and subsequent post-treatment is carried out to obtain the desired benzaldehyde intermediate. The parameters in the reaction are shown in Table 1.

The synthetic route is:

Example 2

The difference from Example 1 is that the reaction temperature of the continuous lithiation reaction is -20° C. and the reaction time is 40 minutes.

Example 3

The difference from Example 1 is: the reaction temperature of the continuous formylation reaction is -20° C. and the reaction time is 40 minutes.

Comparative example 1

The difference from Example 1 is: the benzaldehyde intermediate is prepared by a batch process, and the reaction device is an intermittent reactor.

Table 1

From the above description, it can be seen that the above-mentioned embodiments of the present invention have achieved the following technical effects: compared with traditional batch reactions, the continuous synthesis method provided by the application is conducive to greatly improving the yield of benzaldehyde intermediates .

The above descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and changes. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Claims (15)

1. a kind of continuous device for preparing benzaldehydes intermediate, which is characterized in that the continuous device includes：

Continuous lithiation device (10), the continuous lithiation device (10) are provided with first charging aperture (101) and first Discharge port (102), the first charging aperture (101) is for being added reaction raw materials and organolithium reagent, first discharge port (102) for the product system of continuous lithiation to be continuously discharged；

Continuous formylated device (20), the continuous formylated device (20) are provided with second charging aperture (201), formylation reagent Entrance (202) and the second discharge port (203), the second charging aperture (201) are connected with first discharge port (102), with It is continuously delivered to the product system of the continuous lithiation in the continuous formylated device (20), the formylated examination Agent entrance (202) is used for for formylation reagent, second discharge port (203) to be added by the product body of continuous formylation reaction The continuous discharge of system.

2. continuous device according to claim 1, which is characterized in that the continuous device further includes that dress is continuously quenched Set (30), it is described device (30) continuously is quenched to be provided with third feed inlet (301) and quencher entrance (302), the third into Material mouth (301) is connected with second discharge port (203) and for the product system of the continuous formylation reaction is continuous Ground be delivered to it is described be continuously quenched device (30), the quencher entrance (302) is for being added quencher.

3. continuous device according to claim 2, which is characterized in that the continuous lithiation device (10), described Continuous formylated device (20) and the device (30) that is continuously quenched separately are selected from continuous coil pipe reaction unit or continuous Stir kettle reactor.

4. continuous device according to claim 2 or 3, which is characterized in that the continuous device further includes：

First pre-cooler (40), first pre-cooler (40) are provided with reaction raw materials entrance (401) and pre-cooling material liquid It exports (402)；

Second pre-cooler (50), second pre-cooler (50) is provided with organolithium reagent entrance (501) and pre-cooling is organic Lithium reagent exports (502)；

It is bathed temperature regulating device (41) outside first collet, temperature regulating device (41) is bathed outside first collet for controlling first pre-cooling The temperature of device (40) and second pre-cooler (50)；

Pre-cooling material liquid outlet (402) and the pre-cooling organolithium reagent export (502) with the first charging aperture (101) it is connected, so that pre-cooling material liquid and pre-cooling organolithium reagent are continuously delivered to the continuous lithiation device (10)。

5. continuous device according to claim 4, which is characterized in that the continuous device further includes：

Formylation reagent feeding mechanism (21), the formylation reagent feeding mechanism (21) are provided with formylation reagent supply opening, The formylation reagent supply opening is connected with the formylation reagent entrance (202), for the formylation reagent is continuous It is delivered in the continuous formylated device (20)；

First delivery pump (22), the first delivery pump (22) setting are tried in the formylation reagent supply opening and the formylated On flow path between agent entrance (202).

6. continuous device according to claim 5, which is characterized in that the continuous device further includes：

Third pre-cooler (60), along the flow direction of the formylation reagent, the third pre-cooler (60) is arranged in institute State the downstream of the first delivery pump (22)；And

It is bathed temperature regulating device (61) outside second collet, temperature regulating device (61) is bathed outside second collet for controlling the third pre-cooling Temperature in device (60).

7. continuous device according to claim 6, which is characterized in that the continuous device further includes：

Raw material liquid supply unit (11), the raw material liquid supply unit (11) are provided with material liquid supply opening, and the material liquid supplies Mouth is answered to be connected with the reaction raw materials entrance (401), for the continuously transferring raw material into first pre-cooler (40) Liquid；

Second delivery pump (12), second delivery pump (12) are arranged in the material liquid supply opening and the reaction raw materials entrance (401) on the flow path between.

8. continuous device according to claim 7, which is characterized in that the continuous device further includes：

Organolithium reagent feeding mechanism (13), the organolithium reagent feeding mechanism (13) are provided with organolithium reagent supply opening, The organolithium reagent supply opening is connected with the organolithium reagent entrance (501), and organolithium reagent feeding mechanism (13) is used In the continuously conveying organolithium reagent into second pre-cooler (50)；

Third delivery pump (14), third delivery pump (14) setting are tried in the organolithium reagent supply opening and the organolithium On flow path between agent entrance (501).

9. continuous device according to claim 8, which is characterized in that the continuous device further includes：

Quencher feeding mechanism (31), the quencher feeding mechanism (31) are provided with quencher supply opening, and the quencher supplies Mouth is answered to be connected with the quencher entrance (302), for continuously conveying quencher to described be continuously quenched in device (30)；

4th conveying device (32), the 4th conveying device (32) setting enter in the quencher supply opening with the quencher On flow path between mouth (302).

10. continuous device according to claim 9, which is characterized in that the continuous device further includes：

4th pre-cooler (70), along the flow direction of the quencher, the 4th pre-cooler (70) setting is described the The downstream of four conveying devices (32)；And

It is bathed temperature regulating device (71) outside third collet, temperature regulating device (71) is bathed outside the third collet for controlling the 4th pre-cooling Temperature in device (70).

11. continuous device according to claim 10, which is characterized in that first pre-cooler (40), described Two pre-coolers (50), the third pre-cooler (60) and the 4th pre-cooler (70) are separately selected from continuous disk Tube reaction device continuously stirs autoclave reaction unit.

12. aldehyde radical method is preparing the application in benzaldehydes intermediate in a kind of continuous low temperature lithiumation, which is characterized in that using power Benefit require any one of 1 to 11 described in continuous device prepared, the application includes：

Material liquid and organolithium reagent are continuously delivered to carry out continuous lithiation in continuous lithiation device (10), obtained To lithiated product, continuously the lithiated product is discharged；

It is continuously delivered to the lithiated product and formylation reagent to carry out continuous formylation reaction, obtains the benzaldehydes Intermediate, and the benzaldehydes intermediate is continuously discharged.

13. application according to claim 12, which is characterized in that the reaction temperature of the continuous lithiation be -80~- 30 DEG C, the reaction time is 1~30min；Preferably, the reaction temperature of the continuous lithiation is -60~-50 DEG C, when reaction Between be 5~10min.

14. application according to claim 12 or 13, which is characterized in that the reaction temperature of the continuous formylation reaction It is -80~-30 DEG C, the reaction time is 1~30min；Preferably, the reaction temperature of the continuous formylation reaction is -50~-40 DEG C, the reaction time is 5~10min.

15. application described in any one of 2 to 14 according to claim 1, which is characterized in that the application further includes：It will be described The product system of continuous formylation reaction, which is continuously delivered to continuously be quenched in device (30), carries out continuous quenching reaction, obtains institute State benzaldehydes intermediate.