Continuous flow preparation method and preparation system of Grignard reagent

Abstract

The invention discloses a continuous flow preparation method and a preparation system of a Grignard reagent, and belongs to the technical field of Grignard reagent preparation. The method comprises the following steps: filling magnesium particles with the particle size of 1-10mm in a micro-channel tubular reactor; a halogenated hydrocarbon solution is introduced from the bottom of the microchannel tubular reactor, the Grignard reagent flows out from the top of the microchannel tubular reactor, the retention time of the reaction is 10-45 min, and after the reaction is completed, the Grignard reagent with proper concentration is directly obtained without separating magnesium; the micro-channel tubular reactor is vertically arranged, and filter screens are arranged on a feed port in the bottom and a reaction liquid discharge port in the top of the micro-channel tubular reactor; the magnesium particles are supplemented from the top of the micro-channel tubular reactor. Compared with the prior art, efficiency and safety can be remarkably improved.

Description

Technical Field

[0001] This invention belongs to the field of Grignard reagent preparation technology, and specifically relates to a continuous flow preparation method and system for Grignard reagents. Background Technology

[0002] Grignard reagents (RMgX, where R is a hydrocarbon group and X is a halogen) were discovered by the French chemist Victor Grignard, for whom he was awarded the 1912 Nobel Prize in Chemistry. They are key reagents in organic synthesis for constructing carbon-carbon and carbon-heteroatom bonds. Traditional methods for preparing Grignard reagents often employ batch reactor processes, reacting magnesium shavings with haloalkanes in ether solvents (such as diethyl ether or tetrahydrofuran). This method has several drawbacks: Low reaction efficiency: In batch reactors, the mixing effect of magnesium shavings and haloalkanes is limited, resulting in low mass transfer efficiency and long reaction times. For example, in the preparation of phenyl magnesium bromide (C6H5MgBr), the traditional batch process typically takes 4-8 hours, and the dropping rate of haloalkanes must be strictly controlled during the reaction to prevent runaway reactions. Poor safety: Grignard reagent preparation is a strongly exothermic reaction. In batch reactors, a large amount of heat accumulates in the confined space. If heat dissipation is not timely, the reaction temperature can rise sharply, leading to safety accidents such as material spillage and explosions. According to relevant statistics, accidents caused by uncontrolled Grignard reagent preparation account for 15-20% of organic synthesis accidents in chemical production. Unstable product quality: In batch reactions, it is difficult to ensure that reaction conditions (such as temperature and concentration) are completely consistent between batches, resulting in large fluctuations in the concentration, purity, and other indicators of Grignard reagent products. Taking methylmagnesium chloride (CH3MgCl) as an example, the concentration deviation between different batches can reach ±5%, affecting the stability of subsequent organic synthesis reactions and product quality. In recent years, although some improvements have been made, such as using special stirring devices to improve mixing effects and optimizing cooling systems to enhance heat dissipation, the aforementioned problems have not been fundamentally solved. With the increasing demand for Grignard reagents in the chemical industry and the stringent requirements for safe and efficient production, the development of a new, more efficient, and safer Grignard reagent preparation process is urgently needed. Summary of the Invention To address the aforementioned problems, embodiments of the present invention provide a continuous flow preparation method and system for Grignard reagents, which significantly improves efficiency and safety compared to existing technologies. The technical solution is as follows: On one hand, embodiments of the present invention provide a continuous flow preparation method for Grignard reagent, the method comprising: filling a microchannel tubular reactor with magnesium particles of 1-10 mm in diameter; introducing a haloalkanes solution from the bottom of the microchannel tubular reactor, and allowing the Grignard reagent to flow out from the top of the microchannel tubular reactor, with a reaction residence time of 10-45 min, and obtaining a suitable concentration of Grignard reagent directly without separating magnesium after the reaction is completed.

[0003] The microchannel tubular reactor is vertically arranged, with filters (ensuring magnesium particles cannot pass through) at both the bottom inlet and the top outlet of the reaction liquid. Magnesium particles are added from the top of the reactor. In this embodiment, the size of the magnesium particles is specifically required. If they are too small, the following disadvantages apply: the reaction is too vigorous, the filters are easily clogged, and they tend to flow with the reaction liquid. If they are too large, the following disadvantages apply: the reaction rate is slow, and the filtration effect is poor. Furthermore, in this patent, the Grignard reagent is required to be processed primarily in the lower part of the microchannel tubular reactor to ensure that the magnesium particles in the upper part filter the reaction liquid and replenish the magnesium particles in the lower part. This ensures that magnesium particles are present in excess during the reaction, guaranteeing that magnesium particles are always present in the upper part of the microchannel tubular reactor.

[0004] The magnesium particles can be added during the reaction (the addition of the haloalkane solution needs to be stopped and the liquid level of the haloalkane solution controlled to prevent the liquid from flowing into the magnesium particle addition device) or added between two batches of reaction (preferred).

[0005] In this patent, which can be used for the preparation of conventional Grignard reagents, the halogenated hydrocarbon is a common halogenated hydrocarbon used in the preparation of Grignard reagents (such as chlorides, bromides, iodides, etc.), such as p-chlorobromobenzene, bromooctane, or p-methylchlorobenzene.

[0006] In this embodiment, the solvent for the haloalkane solution is selected from tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, or cyclopentyl methyl ether, preferably tetrahydrofuran. Since the concentration of the haloalkane solution is 0.5-2 mol / L, the concentration of the prepared Grignard reagent is also 0.5-2 mol / L.

[0007] The reaction temperature ranges from 25 to 120°C, depending on the type of Green's reagent; the reaction pressure is less than or equal to 0.6 MPa.

[0008] In this embodiment, the microchannel tubular reactor consists of multiple tubular reactors connected in series from bottom to top, with a height of 1-10m. The Grignard reagent reaction mainly takes place in the lower tubular reactor, while magnesium particles in the upper tubular reactor filter the reaction solution and replenish the magnesium particles in the lower reactor.

[0009] Specifically, the microchannel tubular reactor in this embodiment consists of six to ten (preferably eight) tubular reactors connected in series from bottom to top. The magnesium particles (with a large specific surface area and a microporous structure due to the reaction) in the first tubular reactor (counting from bottom to top) react rapidly with the magnesium particles (the reactants are mainly Green's reagent intermediates and Green's reagent) due to their smaller size compared to other magnesium particles. The reaction conversion rate is 30-50%, and the reaction products serve as catalysts for subsequent reactions. The reaction solution reacts almost completely with the magnesium particles in the second to fourth tubular reactors (the reaction products are mainly Green's reagent), with a conversion rate of 98-100%. As the reaction solution continues to flow upwards, if it carries the magnesium particles upwards, due to the filtering effect of the magnesium particles in the upper tubular reactors, only the tiny magnesium particles can move upwards. These tiny magnesium particles have very high activity and will react rapidly until they disappear.

[0010] Preferably, the magnesium particles provided in this embodiment of the invention have a particle size of 4-10 mm.

[0011] On the other hand, embodiments of the present invention also provide a continuous flow preparation system for Grignard reagents, the system comprising: A reaction vessel is used to dissolve haloalkanes in a solvent to prepare a haloalkanes solution and to deliver the haloalkanes solution to the feed inlet at the bottom of a microchannel tubular reactor. A continuous stirred tank reactor (CSTR) is preferred.

[0012] A microchannel tubular reactor is used for the reaction of halogenated hydrocarbons with magnesium particles. The microchannel tubular reactor is vertically arranged, with filters at the bottom inlet and the top outlet of the reaction liquid, and is filled with magnesium particles with a particle size of 1-10 mm.

[0013] A magnesium particle replenishment device is used to replenish magnesium particles from the top of a microchannel tubular reactor.

[0014] A reaction liquid storage tank is used to collect the Grignard reagent output from the reaction liquid outlet at the top of the microchannel tubular reactor. An inert gas is introduced into the reaction liquid storage tank. The preheater is used to preheat the halohydrocarbon solution in the reactor before sending it to the feed inlet of the microchannel tubular reactor.

[0015] The reactor, preheater, microchannel tubular reactor, and reaction liquid storage tank are connected in sequence by pipelines. The magnesium particle replenishment device is connected to the top of the microchannel tubular reactor (preferably at a connection point higher than the reaction liquid outlet) by a pipeline with a valve (closed when not replenishing). A back pressure valve is installed on the pipeline between the microchannel tubular reactor and the reaction liquid storage tank to control the reaction pressure.

[0016] The microchannel tubular reactor consists of multiple tubular reactors connected in series from bottom to top, with a height of 1-10m. Specifically, it comprises six to ten tubular reactors connected in series from bottom to top. In the first tubular reactor, the magnesium particles, being smaller than those in other reactors, react rapidly, achieving a conversion rate of 30-50%. The reaction products serve as catalysts for subsequent reactions. In the second to fourth tubular reactors, the reaction with the magnesium particles is essentially complete, achieving a conversion rate of 98-100%. As the reaction liquid continues to flow upwards, if it carries the magnesium particles upwards, the filtration effect of the magnesium particles in the upper tubular reactors allows only the extremely small particles to move upwards. These highly reactive particles react rapidly until they disappear.

[0017] The magnesium particle replenishment device is located above the microchannel tubular reactor. It is a high-level structure and is connected to the top of the microchannel tubular reactor through a pipeline with valves.

[0018] The microchannel tubular reactor is made of stainless steel, with an inner diameter of 10 mm or more (preferably 20 mm) and an outer jacket (for individual temperature control). The beneficial effects of the technical solution provided by the embodiments of the present invention are as follows: (1) Significantly improved reaction efficiency: The microchannel reactor greatly improves the mass and heat transfer efficiency of the reaction and shortens the reaction time. Taking the preparation of ethyl magnesium bromide (C2H5MgBr) as an example, the traditional batch process requires 4-8 hours, while this continuous flow process only requires 1.5-3 hours, increasing the production efficiency by 2-3 times. (2) Significantly enhanced safety: The heat of reaction in the continuous flow process (the Green's reagent reaction is exothermic, and some Green's reagent reactions are violent) can be removed in time, avoiding heat accumulation and reducing the risk of runaway reaction. At the same time, the reaction is carried out at atmospheric pressure, reducing the safety hazards caused by high-pressure equipment. According to simulation calculations and actual production verification, the accident rate can be reduced by more than 80% compared with the traditional process. (3) Stable product quality: The precise flow and temperature control of the microchannel reactor ensures the consistency and stability of the reaction conditions, so that the concentration deviation of Grignard reagent products can be controlled within ±5%, the purity is ≥98%, and the product quality fluctuation between batches is minimal, which is conducive to the precise control of subsequent organic synthesis reactions and the improvement of product quality. (4) Obtaining Green's reagent does not require separating magnesium, which is safe (if magnesium is decomposed by adding acid, hydrogen gas will be generated, which poses a safety hazard) and convenient.

[0019] (5) The reaction process does not need to be carried out in an inert gas, which simplifies the process and reduces the difficulty.

[0020] (6) Since tetrahydrofuran has a low boiling point and some of the Green reagents (p-methylchlorobenzene) have a high reaction temperature, the method of this patent is easy to react under pressure (which can reduce the reaction temperature). Attached Figure Description

[0021] Figure 1 This is a schematic diagram of the continuous flow preparation system for Grignard reagents provided in this embodiment of the invention. Detailed Implementation

[0022] To make the objectives, technical solutions, and advantages of the present invention clearer, the present invention will be further described in detail below with reference to the accompanying drawings.

[0023] Example 1: Preparation of p-chlorophenyl magnesium bromide (C6H4ClMgBr) 1. Equipment Installation and Commissioning: Following the technical solution of this patent, a continuous flow reaction device was constructed, including a microchannel tubular reactor (channel size: inner diameter 30mm, 8 tubes connected in series, single tube length 0.6m high), a 5L CSTR (reaction vessel), a plunger metering pump, a circulating heat transfer oil temperature control system, and an online monitoring system. Each piece of equipment was cleaned and commissioned to ensure normal operation and that the flow control and temperature control accuracy met requirements. 2. Raw material preparation: Magnesium granules with a purity of 99.5% and a particle size of 5 μm are directly filled into the reactor; p-chlorobromobenzene (C6H4ClBr) is dissolved in tetrahydrofuran to prepare a 1 mol / L halocarbon solution. 3. Reaction Process: The temperature of the circulating heat transfer oil in the jacket of the microchannel tubular reactor is set to 70℃. After the temperature rises, the plunger metering pump is started to deliver the p-chlorobromobenzene solution to the inlet of the microchannel reactor at a flow rate of 45mL / min. The materials mix and react within the microchannel reactor, with a residence time of approximately 35min. 4. Product separation and analysis: The reaction product flows out from the back pressure valve at the top of the reactor. After detection by an online concentration detector and component analyzer, the concentration of the obtained p-chlorophenyl magnesium bromide product is 1.1 mol / L, the purity is 98.5%, there is no elemental magnesium residue in the product, and the reaction conversion rate is 99%. The concentration of 25 batches of products was tested, and the results are shown in Table 1: Table 1

[0024] The test was conducted from 5 minutes to 30 minutes, and the results are shown in Table 2. Table 2

[0025] As can be seen from Tables 1 and 2, the concentration of the product of this patent is very stable.

[0026] Example 2: Octylmagnesium bromide (C8H) 17 Preparation of MgBr Equipment preparation: The same continuous flow reaction apparatus as in Example 1 is used. Raw material preparation: Prepare bromooctane (C8H4O3) 17 A 0.8 mol / L solution of bromooctane was prepared in tetrahydrofuran. Reaction procedure: The temperature of the circulating heat transfer oil in the jacket of the microchannel tubular reactor was set to 70°C. After the temperature rose, the plunger metering pump was started to deliver the bromooctane solution to the inlet of the microchannel reactor at a flow rate of 40 mL / min. The materials mixed and reacted within the microchannel reactor, with a residence time of approximately 40 min. Product processing and detection: The reaction product flows out from the back pressure valve at the top of the reactor. After detection by an online concentration detector and component analyzer, the concentration of the obtained p-chlorophenyl magnesium bromide product is 0.84 mol / L, the purity is 98.3%, there is no elemental magnesium residue in the product, and the reaction conversion rate is 100%.

[0027] Example 3: Preparation of p-Tolyl Magnesium Chloride (C7H7MgCl) Equipment preparation: The same continuous flow reaction apparatus as in Example 1 is used. Raw material preparation: Prepare a 2 mol / L halocarbon solution of p-methylchlorobenzene (C7H7Cl) in tetrahydrofuran.

[0028] Reaction Operation: The temperature of the circulating heat transfer oil in the jacket of the microchannel tubular reactor is set to 120℃. After the temperature rises, the plunger metering pump is started to deliver the p-methylchlorobenzene solution to the inlet of the microchannel reactor at a flow rate of 25 mL / min. The materials mix and react within the microchannel reactor, with a residence time of approximately 64 min. Product processing and detection: The reaction product flows out from the back pressure valve at the end of the reactor. After being detected by an online concentration detector and component analyzer, the concentration of the obtained p-chlorophenyl magnesium bromide product is 1.95 mol / L, the purity is 98.8%, and the reaction conversion rate is 100%.

[0029] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A continuous flow method for preparing Grignard reagents, characterized in that, The method includes: filling a microchannel tubular reactor with magnesium particles of 1-10 mm in diameter; introducing a haloalkanes solution from the bottom of the microchannel tubular reactor and allowing Grignard reagent to flow out from the top of the reactor; the residence time of the reaction is 10-45 min; after the reaction is completed, a suitable concentration of Grignard reagent is obtained directly without separating magnesium; the microchannel tubular reactor is vertically arranged, and both the inlet at the bottom and the outlet at the top of the reactor are equipped with filters; the magnesium particles are added from the top of the microchannel tubular reactor.

2. The continuous flow preparation method according to claim 1, characterized in that, The solvent for the halohydrocarbon solution is selected from tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, or cyclopentyl methyl ether, and the concentration of the halohydrocarbon solution is 0.5-2 mol / L.

3. The continuous flow preparation method according to claim 1, characterized in that, The reaction temperature is 25-120℃, and the reaction pressure is less than or equal to 0.6MPa.

4. The continuous flow preparation method according to claim 1, characterized in that, The microchannel tubular reactor consists of multiple tubular reactors connected in series from bottom to top, with a height of 1-10m. The Grignard reagent reaction mainly takes place in the lower tubular reactor, while the magnesium particles in the upper tubular reactor filter the reaction solution and replenish the magnesium particles in the lower reactor.

5. The continuous flow preparation method according to claim 1, characterized in that, The microchannel tubular reactor consists of six to ten tubular reactors connected in series from bottom to top. The magnesium particles in the first tubular reactor are smaller than those in the other reactors, resulting in a rapid reaction with a conversion rate of 30-50%. The reaction solution reacts almost completely with the magnesium particles in the second to fourth tubular reactors, achieving a conversion rate of 98-100%. As the reaction solution continues to flow upwards, if it carries the magnesium particles upwards, the filtration effect of the magnesium particles in the upper tubular reactors prevents only the tiny magnesium particles from moving upwards. These tiny magnesium particles, possessing very high activity, react rapidly until they disappear.

6. The continuous flow preparation method according to claim 1, characterized in that, The magnesium particles have a diameter of 4-10 mm.

7. A continuous flow preparation system for Grignard reagents, characterized in that, include: A reaction vessel is used to dissolve haloalkanes in a solvent to prepare a haloalkanes solution and to deliver the haloalkanes solution to the feed inlet at the bottom of a microchannel tubular reactor. A microchannel tubular reactor is used for the reaction of halogenated hydrocarbons with magnesium particles. The microchannel tubular reactor is set vertically, and both the feed inlet at the bottom and the reaction liquid outlet at the top are equipped with filter screens, which are filled with magnesium particles with a particle size of 1-10 mm. Magnesium granule replenishment device for replenishing magnesium granules from the top of a microchannel tubular reactor; A reaction liquid storage tank is used to collect the Grignard reagent output from the reaction liquid outlet at the top of the microchannel tubular reactor; an inert gas is introduced into the reaction liquid storage tank.

8. The continuous flow preparation system according to claim 7, characterized in that, Also includes: The preheater is used to preheat the halohydrocarbon solution in the reactor before sending it to the feed inlet of the microchannel tubular reactor.

9. The continuous flow preparation system according to claim 7, characterized in that, The microchannel tubular reactor is composed of multiple tubular reactors connected in series from bottom to top, and the height of the microchannel tubular reactor is 1-10m.

10. The continuous flow preparation system according to claim 7, characterized in that, The magnesium particle replenishment device is located above the microchannel tubular reactor. It is a high-level structure and is connected to the top of the microchannel tubular reactor through a pipeline with a valve.

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