Method for preparing 2-substituted pyridine derivative through multistage continuous flow micro-reaction

Abstract

The invention relates to a method for preparing a 2-substituted pyridine derivative through a multi-section continuous flow micro reaction, which comprises the following steps of: mixing cyclopentadienylcyclopentadiene cobalt C5H5 (C5H6) Co serving as a catalyst with acrylonitrile and a solvent, then adding part of acetylene required by the reaction, then feeding into a continuous flow micro-reactor, and carrying out continuous flow reaction to obtain the 2-substituted pyridine derivative. The temperature is controlled to be 90-125 DEG C, and the pressure is controlled to be 0.6-1.2 Mpa. Acetylene is continuously introduced from multiple points of the multi-section continuous flow microreactor, the material passes through the last section of reactor and then is subjected to gas-liquid separation, and the liquid part is rectified to obtain the target product 2-substituted pyridine derivative. According to the method, C5H5 (C5H6) Co which is easy to prepare is used as a catalyst, and a multi-section continuous flow microreactor is adopted, so that acetylene is easy to mix with reaction liquid or is dissolved and absorbed, the catalytic reaction of acetylene and acrylonitrile is more facilitated, the conversion rate is increased, and in addition, the safety risk of a reaction system is also greatly reduced.

Description

Technical Field

[0001] The invention belongs to the technical field of preparation of pyridine compounds, and in particular relates to a method for preparing 2-substituted pyridine derivatives through a multi-stage continuous flow micro-reaction. Background Art

[0002] 2-Vinylpyridine (2-VP) is a 2-substituted pyridine derivative, which is an important raw material for the synthesis of styrene butadiene pyridine latex, which is an indispensable raw material for cord fabric in the rubber industry. Regarding the synthesis of 2-vinylpyridine, the existing production process generally uses 2-methylpyridine as the raw material, condenses with formaldehyde or polyformaldehyde, dehydrates at high temperature, and distills to obtain 2-VP. This route has a low single-pass yield and high energy consumption. A large amount of strong alkali is required during the reaction process, which produces a lot of solid waste.

[0003] The direct synthesis of 2-VP using acrylonitrile as raw material has always attracted much attention. Patent US4267329 uses acrylonitrile as raw material and directly catalyzes cyclization with acetylene to prepare 2-vinylpyridine. Due to the addition of a large amount of solvent, the generated 2-VP only accounts for about 4% of the total material, which brings great problems to the subsequent product separation. In addition, the reaction temperature is 150°C, and the raw material acrylonitrile and the product 2-VP are easy to polymerize under the condition of 150°C, which makes it difficult to implement industrialization. Patent EP0064268 uses phenylboron cobalt cyclooctadiene as a catalyst. The catalyst has high activity and the reaction temperature is 50-100°C, but the catalyst is difficult to obtain. In addition, the raw material acetylene is a flammable and explosive item. Especially at slightly higher temperatures and pressures, the stability of acetylene deteriorates, and the safety risk of the pressurized reaction process involving acetylene increases. Improving the intrinsic safety of the synthesis reaction process is also a factor that needs to be paid great attention to.

[0004] Therefore, the process of directly synthesizing 2-VP in one step using acrylonitrile and acetylene as raw materials still needs further research and development. In view of this, the present invention is proposed to solve the problems existing in the prior art. Summary of the invention

[0005] The present invention aims to overcome the defects of the prior art and provide a method for preparing 2-substituted pyridine derivatives by multi-stage continuous flow micro-reaction. The method uses (C5H5(C5H6)Co) which is easy to prepare as a catalyst, adopts a continuous flow micro-reactor, and the reaction system has a small amount of liquid, which greatly reduces the safety risk of the reaction system.

[0006] To achieve the above object, the present invention adopts the following technical solution: A method for preparing 2-substituted pyridine derivatives by multi-stage continuous flow micro-reaction, which uses acrylonitrile and acetylene as raw materials and adopts a continuous flow micro-reactor to prepare 2-substituted pyridine derivatives (2-vinyl pyridine), specifically comprising the following steps: The catalyst-containing acrylonitrile, solvent and acetylene are mixed and reacted at a temperature of 90-125°C and a pressure of 0.6-1.5Mpa through a continuous flow microreactor. After the reaction, the gas and liquid are separated, and the liquid is distilled and rectified (to separate the unreacted acrylonitrile, solvent and product 2-VP. The solvent and unconverted acrylonitrile are recovered and reused) to obtain a 2-substituted pyridine derivative (2-vinyl pyridine); The catalyst is a tetrahydrofuran or 2-methyltetrahydrofuran solution of cyclopentadienylcyclopentadienylcobalt (C5H5(C5H6)Co).

[0007] Specifically, the reaction time may be 5-500 min; the solvent may include one or a mixture of two or more of N-methylpyrrolidone, benzylbenzene, toluene, xylene, etc., and the weight ratio of the solvent to acrylonitrile may be 0.5-5:1. Specifically, the molar ratio of the catalyst to acrylonitrile can be 1:30-300, and the molar ratio of acetylene to acrylonitrile can be 2-4:1, calculated based on the molar amount of cobalt.

[0008] Furthermore, the catalyst can be prepared by the following method: After dicyclopentadienylcobalt ((C5H5)2Co) is dissolved in tetrahydrofuran (THF) or 2-methyltetrahydrofuran, acetic acid (CH3COOH) or concentrated sulfuric acid (H2SO4) or a mixture of acetic acid and concentrated sulfuric acid is added, stirred at room temperature for 12-24 hours, then sodium borohydride (NaBH4) or lithium aluminum hydride (LiAlH4) is added, reacted at room temperature for 2-6 hours, then methanol or ethanol is added to react for 30-60 minutes, filtered, and a tetrahydrofuran or 2-methyltetrahydrofuran solution of C5H5(C5H6)Co is obtained.

[0009] Furthermore, in the process of synthesizing the catalyst, the weight ratio of tetrahydrofuran or 2-methyltetrahydrofuran to dicyclopentadienyl cobalt can be 5-50: 1. The molar ratio of CH3COOH to dicyclopentadienyl cobalt can be 1-1.5: 1, the molar ratio of H2SO4 to dicyclopentadienyl cobalt can be 0.5-0.8: 1. The molar ratio of sodium borohydride to dicyclopentadienyl cobalt can be 0.5-1: 1, and the molar ratio of methanol or ethanol to sodium borohydride can be 3-5: 1.

[0010] Further, in actual operation, the continuous flow microreactor is as follows Figure 1As shown, the acetylene gas for the reaction can be introduced in stages (the acetylene gas for the reaction is introduced from multiple inlets on the reaction tube of the reactor and enters after passing through the gas-liquid mixer), the inner diameter of the reaction tube is 0.6-10 mm, preferably 0.9-1.2 mm, the length of each section of the reaction tube is 5-30 m, preferably 5-15 m, the acrylonitrile containing catalyst and the solvent enter the first section reactor-1, the flow rate is 1-160 ml / min, preferably 3-5 ml / min, the acetylene gas flow rate is 0.0003-3L / min, preferably 5-100 ml / min, the pressure is 0.6-1.5 MPa, the time is 1-10 min, the temperature is 90-125° C., preferably 120-125° C., and then enters the second section reactor-2, the parameters are the same as the first section, the same pipeline is connected in series 5-50 (preferably 10-20, the specific number of series depends on the need to control the reaction conversion rate), the total reaction time is 5-500 min, preferably 25-100 min. In actual use, the length and diameter of the pipeline can also be selected according to actual needs. In addition, the same pipelines can be connected in parallel according to the requirements of production capacity. The series micro-reaction tube can also be a continuous long tube with acetylene inlets installed at certain intervals. After passing through the pipeline, the material enters the gas-liquid separator for gas-liquid separation, the unreacted acetylene is recovered and reused, and the liquid part is distilled to separate the unreacted acrylonitrile, solvent and product 2-VP, and the acrylonitrile single-pass conversion rate is 75-95%.

[0011] The invention provides a catalyst for catalytic synthesis of 2-substituted pyridine derivatives. The catalyst is prepared by the following steps: adding dicyclopentadienyl cobalt into tetrahydrofuran or 2-methyltetrahydrofuran to dissolve the catalyst, adding acetic acid or concentrated sulfuric acid or a mixture of acetic acid and concentrated sulfuric acid, stirring and reacting at room temperature for 12-24 hours, then adding sodium borohydride or lithium aluminum hydride, reacting at room temperature for 2-6 hours, then adding methanol or ethanol, filtering, and obtaining the catalyst.

[0012] The present invention also provides application of the catalyst in catalytic preparation of 2-substituted pyridine derivatives.

[0013] The present invention provides a process for directly synthesizing 2-VP in a step by using acrylonitrile and acetylene as raw materials under the action of a catalyst C5H5(C5H6)Co, and provides a method for preparing the catalyst. The catalyst C5H5(C5H6)Co is characterized by being easy to prepare and having a catalytic reaction temperature of 90-125°C. The present invention adopts a continuous flow microreactor with multi-point acetylene gas inlet, which can be produced continuously, improves the intrinsic safety of the microreactor, meets the needs of safe production development, adopts a multi-point acetylene gas inlet method, can reduce the single-point acetylene introduction amount, facilitates gas-liquid mixing of acrylonitrile or reaction liquid with acetylene, and significantly improves the single-pass conversion rate and reaction efficiency.

[0014] Compared with the prior art, the present invention has the following beneficial effects: The present invention provides a method for preparing 2-substituted pyridine derivatives (2-VP) by cyclization of acrylonitrile and acetylene in one step. The catalyst used is easy to prepare and has high activity. The reaction temperature of acrylonitrile and acetylene is low (90-125°C), which reduces the risk of higher temperature polymerization of raw materials and products. A continuous flow microreactor is used, the gas-liquid contact area is large, and acetylene is introduced by a segmented multi-inlet method, so that acetylene is easy to mix with the reaction liquid or be dissolved and absorbed, which is more conducive to the catalytic reaction of acetylene and acrylonitrile. In addition, the reaction time is short, which avoids the long-term residence of the kettle or tower reactor with large liquid holding capacity, and reduces the occurrence of polymerization and other side reactions. At the same time, the continuous flow microreactor is used, the reaction system holds less liquid, and the safety risk of the reaction system is also reduced. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 Schematic diagram of the structure of the continuous flow microreactor used in the process of the present invention. DETAILED DESCRIPTION

[0016] The technical solution of the present invention is further described in detail below in conjunction with the embodiments, but the protection scope of the present invention is not limited thereto.

[0017] In the following examples, unless otherwise specified, the raw materials used are common commercial products that can be directly purchased or can be prepared by conventional methods in the art.

[0018] Room temperature refers to 25±5°C.

[0019] Example 1 A method for preparing a 2-substituted pyridine derivative (2-vinyl pyridine), which specifically comprises the following steps: 1) Preparation of catalyst: In a 100 ml reaction bottle, add 5.7 g (0.03 mol) of dicyclopentadienylcobalt (C5H5)2Co to 40 g of THF to dissolve, then add 1.8 g (0.03 mol) of acetic acid, stir and react at room temperature for 24 h, then add 1.13 g (0.03 mol) of NaBH4, react at room temperature for 5 h, add 2.9 g (0.09 mol) of methanol, react for 30 min, filter, and obtain a tetrahydrofuran solution of catalyst C5H5(C5H6)Co.

[0020] 2) Synthesis of 2-substituted pyridine derivatives (2-vinyl pyridine) (the structural schematic diagram of the continuous flow microreactor used in the process is shown in Figure 1 shown): The tetrahydrofuran solution of the catalyst C5H5(C5H6)Co (0.03 mol) prepared above, 159.0 g (3 mol) of acrylonitrile and 250 g of toluene were placed in a reaction tank and mixed evenly. The acetylene gas of the reaction was introduced into a continuous flow microreactor in sections. The inner diameter of the reaction tube was 1 mm, and each section was 10 m long. The acrylonitrile containing the catalyst and the solvent was introduced into a gas-liquid mixer through a pump, mixed with acetylene, and then passed through a preheater into the first section reactor (such as Figure 1 Reactor-1 in the reactor), flow rate 3 ml / min (equivalent to acrylonitrile 0.0165mmol / min), acetylene gas flow rate 10ml / min (equivalent to acetylene 0.0026mmol / min), pressure 0.6 Mpa, time about 2.6min, temperature 125℃, and then enter the second reactor (such as Figure 1 Reactor-2 in the reactor), the reaction parameters are the same as the first stage, and 15 similar pipelines are connected in series (n=15, Figure 1 For simplicity, only 5 are marked as a schematic diagram). The total reaction time of the material in the reaction tube is about 34-39 minutes. After gas-liquid separation, the tail gas is recovered, and the liquid is distilled (60-90°C, vacuum degree 0.08-0.09Mpa) and rectified (65-100°C, vacuum degree 0.08-0.095Mpa) to obtain 2-VP257.2g (98.4%, GC determination, area normalization method), the acrylonitrile conversion rate is 80.1%, and the unconverted acrylonitrile and solvent are recovered and reused.

[0021] Example 2 A method for preparing a 2-substituted pyridine derivative (2-vinyl pyridine), which specifically comprises the following steps: 1) Preparation of catalyst In a 100 ml reaction bottle, add 5.7 g (0.03 mol) of dicyclopentadienylcobalt (C5H5)2Co to 35 g of THF to dissolve, add 1.5 g (0.015 mol) of concentrated sulfuric acid, stir and react at room temperature for 24 h, then add 1.0 g (0.026 mol) of NaBH4, react at room temperature for 5 h, add 3.3 g (0.1 mol) of methanol, react for 30 min, filter, and obtain a tetrahydrofuran solution of catalyst C5H5(C5H6)Co. 2) Synthesis of 2-substituted pyridine derivatives (2-vinylpyridine): The tetrahydrofuran solution of the catalyst C5H5(C5H6)Co (0.03 mol) prepared above, 190.8 g (3.6 mol) of acrylonitrile and 150 g of N-methylpyrrolidone were placed in a reaction tank and mixed evenly. The acetylene gas of the reaction was introduced into a continuous flow microreactor in sections. The inner diameter of the reaction tube was 1 mm, and each section was 10 m long. The acrylonitrile containing the catalyst and solvent was introduced into a gas-liquid mixer through a pump, mixed with acetylene, and then passed through a preheater into the first reactor (such as Figure 1 Reactor-1 in the reactor), flow rate 4 ml / min (equivalent to acrylonitrile 0.0326mmol / min), acetylene flow rate 15.2mL / min (equivalent to acetylene 0.0065mmol / min), pressure 1.0 Mpa, time 2min, temperature 125℃, and then enter the second reactor (such as Figure 1 Reactor-2 in the reactor), the reaction parameters are the same as the first stage, 15 similar pipelines are connected in series, and the reaction time of the material in the reaction tube is about 25-30 minutes. After gas-liquid separation, acetylene gas is recovered, and the liquid is distilled (60-90℃, vacuum degree 0.08-0.09Mpa) and rectified (65-100℃, vacuum degree 0.08-0.095Mpa) to obtain 2-VP 271.4 g (97.5%, GC determination, area normalization method), acrylonitrile single-pass conversion rate of 75.1%, unconverted acrylonitrile and solvent are recovered for reuse.

[0022] Example 3 A method for preparing a 2-substituted pyridine derivative (2-vinyl pyridine), which specifically comprises the following steps: 1) Preparation of catalyst In a 100 ml reaction bottle, add 5.7 g (0.03 mol) of dicyclopentadienylcobalt ((C5H5)2Co) to 45 g of THF to dissolve, add 1.5 g (0.015 mol) of concentrated sulfuric acid, stir and react at room temperature for 20 h, then add 1.1 g (0.03 mol) of NaBH4, react at room temperature for 5.5 h, add 3.2 g (0.1 mol) of methanol, react for 40 min, filter, and obtain a tetrahydrofuran solution of the catalyst C5H5(C5H6)Co.

[0023] 2) Synthesis of 2-substituted pyridine derivatives (2-vinylpyridine): The tetrahydrofuran solution of the catalyst C5H5(C5H6)Co (0.03 mol) prepared above, 238.5 g (4.5 mol) of acrylonitrile (catalyst to acrylonitrile 1:150) and 150 g of xylene were placed in a reaction tank and mixed evenly. The reacted acetylene gas was introduced into a continuous flow microreactor in sections. The inner diameter of the reaction tube was 1 mm and the length of each section was 10 m. The acrylonitrile containing the catalyst and solvent was introduced into the gas-liquid mixer through a pump, mixed with acetylene, and then passed through a preheater into the first reactor (such as Figure 1 Reactor-1 in the reactor), flow rate 3ml / min (equivalent to acrylonitrile 0.0255mmol / min), acetylene flow rate 7.4ml / min (0.00319mmol / min), pressure 1.0Mpa, time 2.6min, temperature 125℃, and then enter the second reactor (such as Figure 1 Reactor-2 in the reactor), the reaction parameters are the same as the first stage, 20 similar pipelines are connected in series, and the total reaction time of the material in the reaction tube is about 44-52 min. After gas-liquid separation, acetylene gas is recovered, and the liquid is distilled (60-90°C, vacuum degree 0.08-0.09Mpa) and rectified (65-100°C, vacuum degree 0.08-0.095Mpa) to separate the solvent, unreacted acrylonitrile and product to obtain 2-VP 385.0g (96.1%, GC, area normalization method), acrylonitrile single-pass conversion rate of 78.3%, unconverted acrylonitrile and solvent are recovered for reuse.

[0024] Example 4 A method for preparing a 2-substituted pyridine derivative (2-vinyl pyridine), which specifically comprises the following steps: 1) Preparation of catalyst In a 100 ml reaction bottle, add 5.7 g (0.03 mol) of dicyclopentadienylcobalt ((C5H5)2Co) to 40 g of THF to dissolve, add 1.8 g (0.03 mol) of acetic acid, stir and react at room temperature for 20 h, then add 1.1 g (0.03 mol) of NaBH4, react at room temperature for 6 h, add 3.5 g (0.11 mol) of methanol, react for 30 min, filter, and obtain a tetrahydrofuran solution of the catalyst C5H5(C5H6)Co.

[0025] 2) Synthesis of 2-substituted pyridine derivatives (2-vinylpyridine): The tetrahydrofuran solution of the catalyst C5H5(C5H6)Co (0.03 mol) prepared above, 190.8 g (3.6 mol) of acrylonitrile and 350 g of xylene were placed in a pressure tank and mixed evenly. The acetylene gas of the reaction was introduced into a continuous flow microreactor in sections. The inner diameter of the reaction tube was 1 mm and the length of each section was 10 m. The acrylonitrile containing the catalyst and solvent was introduced into the gas-liquid mixer through a pump, mixed with acetylene, and then passed through a preheater into the first reactor (such as Figure 1 Reactor-1 in the reactor), flow rate 5 ml / min (equivalent to acrylonitrile 0.0258mmol / min), acetylene flow rate 8.9ml / min (0.00384mmol / min), pressure 1.0Mpa, time 1.6min, temperature 120℃, and then enter the second reactor (such as Figure 1 Reactor-2 in the reactor), the reaction parameters are the same as the first stage, 20 similar pipelines are connected in series, and the reaction time of the material in the reaction tube is about 27-32 min. After gas-liquid separation, acetylene gas is recovered, and the liquid is distilled (60-90°C, vacuum degree 0.08-0.09Mpa) and rectified (65-100°C, vacuum degree 0.08-0.095Mpa) to separate the solvent, unreacted acrylonitrile and product 2-VP to obtain 336.0g of 2-VP (96.2%, GC, area normalization method), and the single-pass conversion rate of acrylonitrile is 85.5%. The unconverted acrylonitrile and solvent are recovered for reuse.

Claims

1. A method for preparing 2-substituted pyridine derivatives by multi-stage continuous flow micro-reaction, characterized in that: The steps include: Acrylonitrile containing a catalyst, a solvent and acetylene are mixed, and reacted at a temperature of 90-125° C. and a pressure of 0.6-1.5 MPa through a continuous flow microreactor. After the reaction, gas and liquid are separated, and the liquid is distilled and rectified to obtain the target product; the catalyst is a tetrahydrofuran or 2-methyltetrahydrofuran solution of cyclopentadienylcyclopentadienylcobalt C5H5(C5H6)Co.

2. The method for preparing 2-substituted pyridine derivatives by continuous flow micro-reaction according to claim 1, characterized in that: The reaction time is 5-500 min; the solvent includes one or a mixture of two or more of N-methylpyrrolidone, benzylbenzene, toluene and xylene, and the weight ratio of the solvent to acrylonitrile is 0.5-5:

1.

3. The method for preparing 2-substituted pyridine derivatives by continuous flow micro-reaction according to claim 1, characterized in that: The catalyst is calculated based on the molar amount of cobalt, and the molar ratio of the catalyst to acrylonitrile is 1:30-300.

4. The method for preparing 2-substituted pyridine derivatives by continuous flow micro-reaction according to claim 3, characterized in that: The catalyst is prepared by the following method: Add dicyclopentadienylcobalt (C5H5)2Co into tetrahydrofuran or 2-methyltetrahydrofuran to dissolve, then add acetic acid or concentrated sulfuric acid or a mixture of acetic acid and concentrated sulfuric acid, stir and react at room temperature for 12-24 hours, then add sodium borohydride or lithium aluminum hydride, react at room temperature for 2-6 hours, then add methanol or ethanol, filter and obtain the product.

5. The method for preparing 2-substituted pyridine derivatives by continuous flow micro-reaction according to claim 4, characterized in that: The weight ratio of tetrahydrofuran or 2-methyltetrahydrofuran to dicyclopentadienylcobalt is 5-50:

1.

6. The method for preparing 2-substituted pyridine derivatives by continuous flow micro-reaction according to claim 4, characterized in that: The molar ratio of CH3COOH to dicyclopentadienyl cobalt is 1-1.5:1, and the molar ratio of H2SO4 to dicyclopentadienyl cobalt is 0.5-0.8:

1.

7. The method for preparing 2-substituted pyridine derivatives by continuous flow micro-reaction according to claim 4, characterized in that: The molar ratio of sodium borohydride to dicyclopentadienylcobalt is 0.5-1:1, and the molar ratio of methanol or ethanol to sodium borohydride is 3-5:

1.

8. The method for preparing 2-substituted pyridine derivatives by continuous flow micro-reaction according to claim 4, characterized in that: The acetylene gas for the reaction is introduced in sections, the inner diameter of the reaction tube is 0.6-10mm, the length of each section of the reaction tube is 5-30m, the acrylonitrile containing the catalyst and the solvent enter the first section reactor-1, the flow rate is 1-160 ml / min, the acetylene gas flow rate is 0.0003-3L / min, the pressure is 0.6-1.5Mpa, the time is 1-10min, the temperature is 90-125℃, and then enters the second section reactor-2, the parameters are the same as the first section, the same pipelines are connected in series 5-50, and the total reaction time is 5-500 min.

9. A catalyst for catalytic synthesis of 2-substituted pyridine derivatives, characterized in that: The preparation is carried out through the following steps: dicyclopentadienylcobalt is added to tetrahydrofuran or 2-methyltetrahydrofuran to dissolve, acetic acid or concentrated sulfuric acid or a mixture of acetic acid and concentrated sulfuric acid is added, stirred at room temperature for 12-24 hours, then sodium borohydride or lithium aluminum hydride is added, reacted at room temperature for 2-6 hours, methanol or ethanol is added, and filtered to obtain the product.

10. Use of the catalyst according to claim 9 in catalytic preparation of 2-substituted pyridine derivatives.

Images