Micro-channel continuous flow device for preparing deuterated phenylboronic acid

Abstract

The utility model provides a microchannel continuous flow device for preparing deuterated phenylboronic acid, which relates to the technical field of microchannel reactors, and comprises a material storage system, a feeding system, a series microchannel reaction module and a continuous extraction system, the material storage system comprises a bromobenzene-tetrahydrofuran solution storage device, an n-butyllithium-n-hexane solution storage device, a triisopropyl borate-tetrahydrofuran solution storage device, a hydrochloric acid aqueous solution storage device, an ethyl acetate storage device and a saturated sodium chloride aqueous solution storage device; the series micro-channel reaction module comprises a first plate type micro-channel reactor, a second plate type micro-channel reactor and a third plate type micro-channel reactor which are sequentially communicated in series. The method has the advantages that multi-step continuous reaction can be completed, the reaction is fast, reaction process control points are controlled in a targeted manner, and side reaction can be well inhibited, so that the yield of the deuterated phenylboronic acid is increased, and continuous and efficient synthesis of the target product deuterated phenylboronic acid is realized.

Description

TECHNICAL FIELD

[0001] The utility model relates to microchannel reactor technical field, specifically, relate to a kind of microchannel continuous flow device of preparation deuterated phenylboronic acid. BACKGROUND

[0002] Deuterated phenylboronic acid is an important organic synthesis intermediate, commonly used in suzuki coupling reaction, phthalamidation reaction catalyst, Diels-Alder reaction and other fields.Deuterated phenylboronic acid has good stability, higher reactivity, and has very important application in the synthesis of drugs, organic electroluminescence display (OLED) material, drug controlled-release system.The structure of deuterated phenylboronic acid is as follows:

[0003]

[0004] Deuterated chemicals refer to a class of chemicals with unique physical and chemical properties, in which hydrogen (H) atoms in the compound molecule are replaced by its isotope gas (D) atoms.Deuterated drugs can improve drug safety and have pharmacokinetic advantages such as prolonged efficacy.Deuterated OLED materials can effectively improve the luminous efficiency of the device, increase the stability and life of the device.

[0005] In related technologies, deuterated phenylboronic acid is synthesized using kettle reactors. Using conventional kettle reactors can cause local overheating due to uneven mixing of raw materials, and the reaction process has many side reactions, resulting in low purity and yield of the target product. UTILITY MODEL CONTENT

[0006] The utility model solves the problem of local overheating, low product purity and low yield caused by uneven mixing of raw materials during the synthesis of deuterated phenylboronic acid.

[0007] To solve the above problems, the utility model provides a kind of microchannel continuous flow device of preparation deuterated phenylboronic acid.

[0008] The utility model provides a kind of preparation deuterated phenylboronic acid's microchannel continuous flow device, including material storage system, feed system, series microchannel reaction module and continuous extraction system, material storage system includes bromobenzene-tetrahydrofuran solution storage device, n-butyl lithium-n-hexane solution storage device, borate triisopropyl ester-tetrahydrofuran solution storage device, hydrochloric acid aqueous solution storage device, ethyl acetate storage device and saturated sodium chloride aqueous solution storage device, series microchannel reaction module includes first plate microchannel reactor, second plate microchannel reactor and third plate microchannel reactor that are sequentially connected in series, bromobenzene-tetrahydrofuran solution storage device and n-butyl lithium-n-hexane solution storage device are connected to first plate microchannel reactor by feed system respectively, borate triisopropyl ester-tetrahydrofuran solution storage device is connected to second plate microchannel reactor by feed system, hydrochloric acid aqueous solution storage device is connected to third plate microchannel reactor by feed system, and third plate microchannel reactor, ethyl acetate storage device and saturated sodium chloride aqueous solution storage device are connected to continuous extraction system respectively.

[0009] Optionally, the flow direction of the material flowing into the continuous extraction system from the ethyl acetate storage device and the saturated sodium chloride aqueous solution storage device is opposite.

[0010] Optionally, the microchannel continuous flow device for preparing deuterated phenylboronic acid further comprises an analysis and detection system, which is connected to the bromobenzene-tetrahydrofuran solution storage device, the n-butyl lithium-n-hexane solution storage device, and the borate triisopropyl ester-tetrahydrofuran solution storage device, respectively, for intermittently detecting the moisture content of the reactant material in the bromobenzene-tetrahydrofuran solution storage device, the n-butyl lithium-n-hexane solution storage device, and the borate triisopropyl ester-tetrahydrofuran solution storage device.

[0011] Optionally, the microchannel continuous flow device for preparing deuterated phenylboronic acid further comprises a gas supply system for providing nitrogen or inert gas protection to the microchannel continuous flow device for preparing deuterated phenylboronic acid.

[0012] Optionally, the gas supply system comprises a gas storage device, a gas supply pipeline, and a bubbler.

[0013] Optionally, the microchannel continuous flow device for preparing deuterated phenylboronic acid further comprises a pre-cooling system, which is connected to the bromobenzene-tetrahydrofuran solution storage device, the n-butyl lithium-n-hexane solution storage device, and the borate triisopropyl ester-tetrahydrofuran solution storage device, respectively, for cooling the reactant material in the bromobenzene-tetrahydrofuran solution storage device, the n-butyl lithium-n-hexane solution storage device, and the borate triisopropyl ester-tetrahydrofuran solution storage device.

[0014] Optionally, the micro-channel continuous flow device for preparing deuterated phenylboronic acid further comprises a temperature control system connected to the series micro-channel reaction module for controlling the reaction temperature in the series micro-channel reaction module.

[0015] Optionally, the temperature control system comprises a high and low temperature all-in-one machine and an electric couple temperature sensor.

[0016] Optionally, the micro-channel continuous flow device for preparing deuterated phenylboronic acid further comprises a product storage device, and the continuous extraction system is communicated to the product storage device.

[0017] Optionally, the third plate micro-channel reactor is communicated to the side of the continuous extraction system, and the product storage device is communicated to the side opposite to the continuous extraction system.

[0018] The micro-channel continuous flow device for preparing deuterated phenylboronic acid has the following beneficial effects: the plate micro-channel reactor is used for multi-stage series connection to form a series micro-channel reaction module, and multiple continuous reactions can be completed; the material storage system and the feeding system are arranged to supply materials to the series micro-channel reaction module; the bromobenzene-tetrahydrofuran solution and the n-butyl lithium-n-hexane solution are fed into the first plate micro-channel reactor to form a lithium reagent intermediate through lithium halogen exchange; the lithium reagent intermediate and the boronic acid triisopropyl ester-tetrahydrofuran solution continue to react in the second plate micro-channel reactor; the reaction liquid and the hydrochloric acid aqueous solution are fed into the third plate micro-channel reactor to generate deuterated phenylboronic acid through hydrochloric acid acidification; the materials in the plate micro-channel reactor react quickly in the reactor, and deuterated phenylboronic acid can be synthesized economically and efficiently under the premise of safety and environmental protection; the materials in the plate micro-channel reactor have a very short contact time in the reactor, and different reaction reagents are added in different plate micro-channel reactors in sequence, so that the reaction process control points are controlled in a targeted manner, the occurrence of side reactions can be well inhibited, the yield of deuterated phenylboronic acid is improved, and the target product can be continuously and efficiently synthesized; the continuous extraction system is used for simple purification of the target product deuterated phenylboronic acid; two non-miscible two-phase solvents, ethyl acetate and saturated sodium chloride aqueous solution, are used for countercurrent flow, one phase is an ethyl acetate organic phase capable of dissolving the product and part of water-insoluble impurities, and the other phase is a salt water phase of the sodium chloride aqueous solution capable of washing away water-soluble impurities, so that the excess water-soluble impurities in the reaction liquid are washed, and a relatively purified deuterated phenylboronic acid product is obtained; the device is simple, and the cost is low. BRIEF DESCRIPTION OF DRAWINGS

[0019] Figure 1 The micro-channel continuous flow device for preparing deuterated phenylboronic acid is a structure schematic view of an embodiment of the utility model;

[0020] Mark explanation:

[0021] 11, bromobenzene-tetrahydrofuran solution storage device; 12, n-butyllithium-n-hexane solution storage device; 13, boronate triisopropyl-tetrahydrofuran solution storage device; 14, hydrochloric acid aqueous solution storage device; 15, ethyl acetate storage device; 16, saturated sodium chloride aqueous solution storage device; 17, product storage device; 2, analytical detection system; 3, gas supply system; 4, precooling system; 5, feeding system, 6, series micro-channel reaction module; 61, first plate micro-channel reactor; 62, second plate micro-channel reactor; 63, third plate micro-channel reactor; 7, temperature control system; 8, continuous extraction system. DETAILED DESCRIPTION

[0022] In order to make the above objectives, characteristics and advantages of the present application more obvious and easy to understand, the specific embodiments of the present application will be described in detail below with reference to the drawings. Although some embodiments of the present application are shown in the drawings, it should be understood that the present application can be implemented in various forms, and should not be interpreted as being limited to the embodiments described herein, on the contrary, these embodiments are provided to make the present application more thorough and complete. It should be understood that the drawings and embodiments of the present application are only for illustrative purposes, and are not intended to limit the scope of protection of the present application.

[0023] The term "comprising" and its variants used herein are open-ended, i.e. "including but not limited to"; the term "based on" is "at least partially based on"; the term "one embodiment" means "at least one embodiment"; the term "another embodiment" means "at least one additional embodiment"; the term "some embodiments" means "at least some embodiments"; the term "optionally" means "optional embodiment". Related definitions of other terms will be given in the following description. It should be noted that the "first", "second", etc. concepts mentioned in the present application are only used to distinguish different devices, modules or units, and are not intended to limit the functions performed by these devices, modules or units or their mutual dependency.

[0024] It should be noted that the modification of "one" or "multiple" mentioned in the present application is illustrative and not limiting, and those skilled in the art should understand that unless otherwise explicitly indicated in the context, it should be understood as "one or more".

[0025] In the related art, in the existing synthesis method of phenylboronic acid, the existing process preparation method of ordinary phenylboronic acid at the present stage is mainly Grignard reagent kettle type reaction method and organic lithium reagent kettle type reaction method, which has the phenomenon that by-products are not easy to separate and purify, and the yield of the product and the utilization rate of bromobenzene are relatively low. For example, when using the Grignard reagent kettle type reaction method, the yield is about 50-70%; when using the organic lithium reagent kettle type reaction method, the yield is about 70-80%. However, for deuterated phenylboronic acid, since the price of deuterated bromobenzene as raw material is relatively high, the above Grignard reagent kettle type reaction method and organic lithium reagent kettle type reaction method with low deuterated bromobenzene utilization rate are not suitable for industrial manufacturing of deuterated phenylboronic acid.

[0026] In view of the problems in the above related art, the embodiment provides a micro-channel continuous flow device for preparing deuterated phenylboronic acid.

[0027] As shown in Figure 1 The micro-channel continuous flow device for preparing deuterated phenylboronic acid provided by the embodiment of the utility model, including material storage system, feed system 5, series micro-channel reaction module 6 and continuous extraction system 8, material storage system includes bromobenzene-tetrahydrofuran solution storage device 11, n-butyl lithium-n-hexane solution storage device 12, borate triisopropyl ester-tetrahydrofuran solution storage device 13, hydrochloric acid aqueous solution storage device 14, ethyl acetate storage device 15 and saturated sodium chloride aqueous solution storage device 16, series micro-channel reaction module 6 includes first plate type micro-channel reactor 61, second plate type micro-channel reactor 62 and third plate type micro-channel reactor 63 that are sequentially connected in series, bromobenzene-tetrahydrofuran solution storage device 11 and n-butyl lithium-n-hexane solution storage device 12 are connected to first plate type micro-channel reactor 61 through feed system 5 respectively, borate triisopropyl ester-tetrahydrofuran solution storage device 13 is connected to second plate type micro-channel reactor 62 through feed system 5, hydrochloric acid aqueous solution storage device 14 is connected to third plate type micro-channel reactor 63 through feed system 5, and third plate type micro-channel reactor 63, ethyl acetate storage device 15 and saturated sodium chloride aqueous solution storage device 16 are connected to continuous extraction system 8 respectively.

[0028] In this embodiment, a set of serial micro-channel reaction modules 6 is formed by using the plate micro-channel reactor in multi-stage series, which can complete multi-step continuous reaction. The material storage system and the feeding system 5 supply materials to the serial micro-channel reaction modules 6, and the bromobenzene-tetrahydrofuran solution and the n-butyl lithium-n-hexane solution are fed into the first plate micro-channel reactor 61 to form lithium reagent intermediates through lithium halogen exchange. The lithium reagent intermediates and the boronic acid triisopropyl ester-tetrahydrofuran solution continue to react in the second plate micro-channel reactor 62. The reaction liquid and the hydrochloric acid aqueous solution are fed into the third plate micro-channel reactor 63 to generate deuterated phenylboronic acid through hydrochloric acid acidification. The materials in the plate micro-channel reactor rapidly react in the reactor, which can economically and efficiently synthesize deuterated phenylboronic acid under the premise of safety and environmental protection. Since the materials in the plate micro-channel reactor have a very short contact time in the reactor, and different reaction reagents are added in different plate micro-channel reactors, the reaction process control points can be controlled in a targeted manner, which can well inhibit the occurrence of side reactions, thereby improving the yield of deuterated phenylboronic acid and realizing continuous and efficient synthesis of the target product. The continuous extraction system 8 is used for simple purification of the target product deuterated phenylboronic acid. Two streams of immiscible two-phase solvents, ethyl acetate and saturated sodium chloride aqueous solution, flow in. One phase is the ethyl acetate organic phase, which can dissolve the product and part of the water-insoluble impurities. The other phase is the salt water phase of the sodium chloride aqueous solution, which can wash away the water-soluble impurities. The excess water-soluble impurities in the reaction liquid are washed, and finally the purified deuterated phenylboronic acid product is obtained. The equipment is simple and the cost is low. Subsequently, further beating and purification can be performed to obtain a more purified deuterated phenylboronic acid product.

[0029] Specifically, the continuous extraction system 8 can be composed of a commercially available liquid-liquid rotating disc extraction column, which is used for continuous extraction of the reaction liquid after the reaction in the serial micro-channel reaction modules 6.

[0030] Specifically, the material storage system includes a plurality of independent solution storage devices, which can be made of glass, stainless steel, enamel and / or polytetrafluoroethylene. Since some materials can corrode glass, such as strong alkali solution, the material of the solution storage device can be replaced with stainless steel or polytetrafluoroethylene, etc. according to the properties of different raw materials.

[0031] Specifically, the feeding system 5 can include a plurality of plunger pumps, peristaltic pumps and / or diaphragm pumps according to the properties of the materials.

[0032] The first plate micro-channel reactor 61, the second plate micro-channel reactor 62 and the third plate micro-channel reactor 63 can all be umbrella-shaped plate micro-channel reactors. Such reactors are made of special channels processed on metal plates, which include heart-shaped, umbrella-shaped or O-shaped channels, and have the characteristics of double-sided heat exchange and pressure resistance.

[0033] Optionally, the flow direction of the material flowing into the continuous extraction system 8 from the ethyl acetate storage device 15 and the saturated sodium chloride aqueous solution storage device 16 is opposite. That is, the two side walls of the continuous extraction system 8 connected to the ethyl acetate storage device 15 and the saturated sodium chloride aqueous solution storage device 16 are opposite.

[0034] In this optional embodiment, the two immiscible two-phase solvents, ethyl acetate and saturated sodium chloride aqueous solution, are countercurrent, which can quickly separate the product and the impurities insoluble in water from the impurities soluble in water, and quickly purify the deuterated phenylboronic acid product.

[0035] Optionally, the micro-channel continuous flow device for preparing deuterated phenylboronic acid further comprises an analysis and detection system 2 connected to the bromobenzene-tetrahydrofuran solution storage device 11, the n-butyllithium-n-hexane solution storage device 12 and the boronic acid triisopropyl ester-tetrahydrofuran solution storage device 13, respectively, for intermittently detecting the water content of the reactant in the bromobenzene-tetrahydrofuran solution storage device 11, the n-butyllithium-n-hexane solution storage device 12 and the boronic acid triisopropyl ester-tetrahydrofuran solution storage device 13.

[0036] In this optional embodiment, the water content of the material is controlled at a low level to avoid excessive water in the reaction system from generating a large amount of by-products. If the analysis and detection system 2 detects that the water content is too high, activated 4A molecular sieves can be added to dry the material.

[0037] Specifically, the analysis and detection system 2 comprises a Karl Fischer moisture titrator, an analytical balance (sensitivity is 0.1 mg), a microsyringe (range is 10 μL), a syringe (range is 2 mL), distilled water, and volumetric method two-component Karl Fischer reagent.

[0038] Optionally, the micro-channel continuous flow device for preparing deuterated phenylboronic acid further comprises a gas supply system 3 for providing nitrogen or inert gas protection to the micro-channel continuous flow device for preparing deuterated phenylboronic acid.

[0039] In this optional embodiment, the entire system is provided with nitrogen or inert gas protection by using the gas supply system 3, which ensures that air does not enter the material, further avoids the oxygen and water vapor in the air from causing side reactions such as oxidation and hydrolysis of the raw materials, and further avoids the water vapor from causing excessive protons to enter the reaction system during the reaction process, thereby further generating a large amount of deuterated benzene by-products and greatly reducing the yield.

[0040] Specifically, the gas supply system 3 includes but is not limited to the supply of inert gases such as nitrogen or argon, and can also include the supply of hydrogen, carbon monoxide, etc. Different gas cylinders can be replaced according to the type of reaction to achieve different gas supply.

[0041] Optionally, the gas supply system 3 comprises a gas storage device, a gas supply pipeline and a bubbler.

[0042] Optionally, the micro-channel continuous flow device for preparing deuterated phenylboronic acid further comprises a pre-cooling system 4, which is connected to the bromobenzene-tetrahydrofuran solution storage device 11, the n-butyllithium-n-hexane solution storage device 12 and the boronic acid triisopropyl ester-tetrahydrofuran solution storage device 13 respectively, for cooling the reactants in the bromobenzene-tetrahydrofuran solution storage device 11, the n-butyllithium-n-hexane solution storage device 12 and the boronic acid triisopropyl ester-tetrahydrofuran solution storage device 13.

[0043] In this optional embodiment, the temperature of the reaction system in the series micro-channel reaction module 6 is low, and the material is cooled in advance to avoid large fluctuations in the temperature of the reaction system.

[0044] Optionally, the micro-channel continuous flow device for preparing deuterated phenylboronic acid further comprises a temperature control system 7, which is connected to the series micro-channel reaction module 6, for controlling the reaction temperature in the series micro-channel reaction module 6.

[0045] In this optional embodiment, the temperature control system 7 is used to adjust and control the temperature of the pre-cooling system 4 and the series micro-channel reaction module 6, so as to adjust the temperature of the reaction system and control the reaction system to proceed at a suitable temperature.

[0046] Optionally, the temperature control system 7 comprises a high and low temperature all-in-one machine and an electrically coupled temperature sensor.

[0047] Optionally, the micro-channel continuous flow device for preparing deuterated phenylboronic acid further comprises a product storage device 17, and the continuous extraction system 8 is connected to the side of the product storage device 17.

[0048] Optionally, the third plate-type micro-channel reactor 63 is connected to the side of the continuous extraction system 8, and the side of the product storage device 17 connected to the continuous extraction system 8 is opposite to the side of the third plate-type micro-channel reactor 63.

[0049] In this optional embodiment, the product of the third plate-type micro-channel reactor 63 enters from one side of the continuous extraction system 8 and flows out from the opposite side into the product storage device 17, so that the product of the third plate-type micro-channel reactor 63 can be sufficiently purified in the continuous extraction system 8; if the side of the third plate-type micro-channel reactor 63 connected to the continuous extraction system 8 and the side of the product storage device 17 connected to the continuous extraction system 8 are the same or adjacent, the product of the third plate-type micro-channel reactor 63 may not be purified before flowing into the product storage device 17, resulting in too many impurities in the deuterated phenylboronic acid product and low purity.

[0050] Although the utility model discloses as above, the protection scope of the utility model is not limited to this only.The person skilled in the art can make various changes and modifications without departing from the spirit and scope of the utility model, and these changes and modifications will all fall into the protection scope of the utility model.

Claims

1. A microchannel continuous flow apparatus for preparing deuterated phenylboronic acid, characterized in that, The system includes a material storage system, a feeding system (5), a series microchannel reaction module (6), and a continuous extraction system (8). The material storage system includes a bromobenzene-tetrahydrofuran solution storage device (11), a n-butyllithium-n-hexane solution storage device (12), a triisopropyl borate-tetrahydrofuran solution storage device (13), a hydrochloric acid aqueous solution storage device (14), an ethyl acetate storage device (15), and a saturated sodium chloride aqueous solution storage device (16). The series microchannel reaction module (6) includes a first plate microchannel reactor (61), a second plate microchannel reactor (62), and a third plate microchannel reactor (63) connected in series. The furan solution storage device (11) and the n-butyllithium-n-hexane solution storage device (12) are respectively connected to the first plate microchannel reactor (61) through the feed system (5). The triisopropyl borate-tetrahydrofuran solution storage device (13) is connected to the second plate microchannel reactor (62) through the feed system (5). The hydrochloric acid aqueous solution storage device (14) is connected to the third plate microchannel reactor (63) through the feed system (5). The third plate microchannel reactor (63), the ethyl acetate storage device (15), and the saturated sodium chloride aqueous solution storage device (16) are respectively connected to the continuous extraction system (8).

2. The microchannel continuous flow apparatus for preparing deuterated phenylboronic acid according to claim 1, characterized in that, The materials flowing into the continuous extraction system (8) from the ethyl acetate storage device (15) and the saturated sodium chloride aqueous solution storage device (16) are in opposite directions.

3. The microchannel continuous flow apparatus for preparing deuterated phenylboronic acid according to claim 1, characterized in that, The microchannel continuous flow apparatus for preparing deuterated phenylboronic acid also includes an analytical detection system (2), which is connected to the bromobenzene-tetrahydrofuran solution storage device (11), the n-butyllithium-n-hexane solution storage device (12), and the triisopropyl borate-tetrahydrofuran solution storage device (13), respectively, for intermittently detecting the moisture content of the reactants in the bromobenzene-tetrahydrofuran solution storage device (11), the n-butyllithium-n-hexane solution storage device (12), and the triisopropyl borate-tetrahydrofuran solution storage device (13).

4. The microchannel continuous flow apparatus for preparing deuterated phenylboronic acid according to claim 1, characterized in that, The microchannel continuous flow apparatus for preparing deuterated phenylboronic acid also includes a gas supply system (3), which is used to provide nitrogen or inert gas protection to the microchannel continuous flow apparatus for preparing deuterated phenylboronic acid.

5. The microchannel continuous flow apparatus for preparing deuterated phenylboronic acid according to claim 4, characterized in that, The gas supply system (3) includes a gas storage device, a gas supply pipeline and a bubbler.

6. The microchannel continuous flow apparatus for preparing deuterated phenylboronic acid according to claim 1, characterized in that, The microchannel continuous flow apparatus for preparing deuterated phenylboronic acid also includes a precooling system (4), which is connected to the bromobenzene-tetrahydrofuran solution storage device (11), the n-butyllithium-n-hexane solution storage device (12), and the triisopropyl borate-tetrahydrofuran solution storage device (13), respectively, and is used to cool the reactants in the bromobenzene-tetrahydrofuran solution storage device (11), the n-butyllithium-n-hexane solution storage device (12), and the triisopropyl borate-tetrahydrofuran solution storage device (13).

7. The microchannel continuous flow apparatus for preparing deuterated phenylboronic acid according to claim 1, characterized in that, The microchannel continuous flow apparatus for preparing deuterated phenylboronic acid also includes a temperature control system (7), which is connected to a series microchannel reaction module (6) and is used to control the reaction temperature within the series microchannel reaction module (6).

8. The microchannel continuous flow apparatus for preparing deuterated phenylboronic acid according to claim 7, characterized in that, The temperature control system (7) includes a high and low temperature integrated unit and a thermocouple temperature sensor.

9. The microchannel continuous flow apparatus for preparing deuterated phenylboronic acid according to claim 1, characterized in that, The microchannel continuous flow apparatus for preparing deuterated phenylboronic acid also includes a product storage device (17), and the continuous extraction system (8) is connected to the product storage device (17).

10. The microchannel continuous flow apparatus for preparing deuterated phenylboronic acid according to claim 9, characterized in that, The third plate microchannel reactor (63) is connected to the side of the continuous extraction system (8) and is opposite to the side of the product storage device (17) connected to the continuous extraction system (8).

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